Abstract
Repair of acute kidney injury (AKI) is a typical example of renal regeneration. AKI is characterized by tubular cell death, peritubular capillary (PTC) thinning, and immune system activation. After renal tubule injury, resident renal progenitor cells, or renal tubule dedifferentiation, give rise to renal progenitor cells and repair the damaged renal tubule through proliferation and differentiation. Mesenchymal stem cells (MSCs) also play an important role in renal tubular repair. AKI leads to sparse PTC, affecting the supply of nutrients and oxygen and indirectly aggravating AKI. Therefore, repairing PTC is important for the prognosis of AKI. The activation of the immune system is conducive for the body to clear the necrotic cells and debris generated by AKI; however, if the immune activation is too strong or lengthy, it will cause damage to renal tubule cells or inhibit their repair. Macrophages have been shown to play an important role in the repair of kidney injury. Traditional Chinese medicine (TCM) has unique advantages in the treatment of AKI and a series of studies have been conducted on the topic in recent years. Herein, the role of TCM in promoting the repair of renal injury and its molecular mechanism is discussed from three perspectives: repair of renal tubular epithelial cells, repair of PTC, and regulation of macrophages to provide a reference for the treatment and mechanistic research of AKI.
Similar content being viewed by others
Introduction
Acute kidney injury (AKI) is a serious clinical syndrome with high morbidity and mortality, and no ideal clinical treatment [1]. AKI is primarily caused by proximal renal tubule injury, accompanied by microvascular injury and immune activation [2]. The kidneys are able to repair damage. Several studies have shown that kidney injury can activate resident kidney progenitor or tubular cells to dedifferentiate into kidney progenitor cells, promote their proliferation and differentiation, and participate in kidney injury repair [3, 4]. Additionally, studies have revealed that mesenchymal stem cells (MSCs) can promote the repair of kidney injury by regulating the innate immune balance [5]. In addition, MSCs can migrate to the kidneys, differentiate into renal parenchymal cells, and promote the regeneration of damaged kidney cells [6, 7]. AKI is typically accompanied by perirenal capillary damage, resulting in renal tubule hypoxia, which crucially affects the self-repair ability of the renal tubules and is an important factor in AKI-chronic kidney disease (CKD) transformation [8]. During AKI, various factors participate in the activation and recruitment of immune cells to the injured kidneys. These factors include damage-associated molecular patterns (DAMPs), hypoxia-inducible factors (HIFs), adhesion molecules, chemokines, and cytokines [9, 10] Immune cells of the innate and adaptive immune systems, such as neutrophils, dendritic cells (DCs), macrophages, and lymphocytes, are involved in the pathogenesis of kidney injury, and some of their subgroups are involved in the repair process [9, 10]. Traditional Chinese medicine (TCM) provides a theoretical basis for the treatment of AKI, vascular injury, and immune regulation. Herein, the research progress of TCM in promoting AKI repair is discussed from three perspectives: repair of renal tubular epithelial cells, repair of peritubular capillaries (PTC), and regulation of immune cells.
Kidney injury repair and stem cells
Stem cells are self-renewing cells with an infinite or immortal capacity to produce at least one type of highly differentiated daughter cell. Depending on their source, stem cells are divided into embryonic, adult, and induced pluripotent stem cells. Stem cells play a central role in the regenerative processes. Several adult organs contain stem cells. These cells are found in adult tissues and can differentiate into any cell type in the original organ. In contrast to embryonic stem cells, these cells are considered pluripotent instead of omnipotent. Progenitor cells are assumed to have a more limited differentiation capacity than stem cells and can differentiate into one or more cell types of the original tissue, however, can only replicate a limited number of times. In the kidneys, progenitor cells are typically at rest, and when activated by stimulation, they proliferate, eventually migrating to the site of injury and constructing novel renal tubules [3, 4]. I Currently, at least two types of kidney progenitor cells, CD133 + CD24 + and Sox9 + , are involved in kidney injury repair. Additionally, MSCs play an important role in AKI repair. Figure 1 describes how adult stem cells, including Renal progenitor cells and MSCs, are involved in the repair of AKI and how TCM is involved in the repair of AKI through the regulation of stem cells.
Mechanism of adult stem cells in acute renal injury repair and traditional Chinese medicine intervention
Renal progenitor cells
Renal progenitor cells participate in renal injury repair
In the early 1900s, Jean Oliver described the process of renal tubular epithelial cell replication, replacing lost cells, and repairing injured epithelium [11]. Chang-Panesso et al. reported that after tubular death caused by AKI, tubular cells proliferate rapidly to restore the number of tubular cells, peaking 48 h after the injury. Pedigree tracing experiments have confirmed that these repair cells originate from the renal tubule instead of from circulating or interstitial progenitors [12]. Evidence suggests that the dedifferentiated epithelial cells that survive AKI have the same repair capacity [13,14,15,16]. In addition, a group of WNT-responsive or PAX2 positive or CD133-, CD24-, or SOX9-positive intracellular progenitor cells selectively proliferate and differentiate into renal tubular cells [17,18,19]. CD133 + CD24 + cells have been identified as the cellular mediators of proximal tubular repair in mice and humans, suggesting the possibility of an intratubular progenitor population [20]. Recently, several studies have shown that injury-induced Sox9 activation acts as a regenerative signal. Several studies have confirmed that Sox9 + renal tubular cells have progenitor cell properties, which increase rapidly after kidney injury and then participate in the repair of kidney injury [19, 21,22,23]. Briefly, following kidney injury, the renal tubules are initially damaged, prompting the proliferation of renal progenitor cells, which then contribute to the repair of damage.
Depending on the severity of the injury or compromised bodily functions, such as aging, kidney damage may not be repaired promptly, potentially leading to serious healthoutcomes. Several studies have shown that exogenous kidney progenitor cells participate in the repair of kidney injury and promote the recovery of kidney function [24, 25]. However, the clinical application of exogenous progenitor cells faces challenges due to immune rejection and safety problems, making it difficult to advance. The activation of endogenous kidney progenitor cells is a more promising option.
Potential targets for regulating renal progenitor cells
Low Sox9 expression has been observed in adult kidneys. However, when cellular stress or injury occurs, Sox9 undergoes transcriptional activation [21,22,23]. Kumar et al. discovered that in acutely injured mammalian kidneys, the activation and regulation of Sox9 are mediated by the EGFR/ERK1/2 signaling pathway and HIFA [4]. Ma et al. showed that kidney resection-induced kidney injury triggers the activation of Sox9 expression through the Notch signaling pathway, thereby facilitating the repair of the injury [22]. Similarly, Kim et al. observed that CDCKl5 exerts suppressive effects on Sox9, a transcriptional regulator associated with cell survival, through phosphorylation-dependent mechanisms in the context of renal injury [26]. Furthermore, Kim et al. identified an essential role for the ZFP24 protein in the activation of Sox9 during AKI [27]. These studies provide evidence of the effects of SOX9 expression or phosphorylation on renal injury repair.
A study conducted by Ohnishi et al. showed that HIF-1a activated the CD133 promoter in human embryonic kidney (HEK) 293 cells and the colon cancer cell line WiDr. One of two E-twenty-six (ETS) binding sites (EBSs) in the P5 region is required for its promoter activity induced by HIF-1a and HIF-2a. Immunoprecipitation experiments revealed that HIF-1a physically interacts with Elk1; however, HIF-2a does not interact with Elk1 or ETS1 [28]. Bussolati et al. reported that when CD133 + cells were cultured under hypoxiccondition in 1% oxygen, CD133 expression was upregulated after 24 h and was maintained for up to 72 h. Compared with CD133 + cells from the papillary region, CD133 + cells cultured under hypoxicconditions promote the rapid upregulation of HIF1, but not HIF2, which is constitutively expressed [29]. Maehara et al. demonstrated that metformin can inhibit the expression of CD133 in hepatocellular carcinoma cell lines through the AMPK-CEBP-β pathway [30].
TCM ameliorates kidney injury repair involved in the regulation of endogenous kidney progenitor cells
Wu et al. showed that 7-hydroxycoumarin (7-HC, also known as umbelliferone, commonly found in Chinese herbs such as Eucommiae Cortex, Prunellae Spica, Radix Angelicae Biseratae) inhibits necrosis and promotes the expression of Sox9 and proliferation of renal tubular epithelial cells, thus participating in kidney injury repair [31]. Experimental data have demonstrated that knockdown of Sox9 attenuates the 7-HC suppressive effects on KIM-1 and reverse the 7-HC stimulatory effects on cyclin D1 expression in HK-2 cells treated with cisplatin, indicating that the AKI protective mechanism stimulated by 7-HC may be mediated through Sox9 [31]. However, the mechanism by which 7-HC affects Sox9 expression remains unclear.
Zheng et al. used paraquat to induce AKI and isorhapontigenin as an intervention. This study showed that isorhapontigenin affected TOLLIP expression through the upregulation of Sox9, thereby reducing apoptosis and oxidative stress [32]. In NRK-52E cells, the overexpression of SOX9 demonstrated a mitigating effect on paraquat-induced apoptosis and oxidative stress. Conversely, SOX9 knockdown reduced the protective effects of isorhapontigenin. These findings suggest that SOX9 plays a crucial role in the therapeutic potential of isorhapontigenin for the treatment of paraquat-induced AKI [32].
Huang et al. used 5/6 nephrectomy to prepare a chronic renal failure model and demonstrated that icariin reduced creatinine and urea levels and promoted renal function recovery. Furthermore, icariin significantly increased the expression of CD133 and CD24 in renal tubular cells and promoted the proliferation of CD133 + /CD24 + renal progenitor cells [33].
All the aforementioned studies used AKI monomers to intervene and promote kidney injury repair by promoting the expression of kidney progenitor cell markers. The mechanism through which these monomers affect the expression of SOX9 or CD133\CD24 requires further investigation.
MSCs promote renal injury repair
MSCs are multipotent cells derived from various sources such as the bone marrow, adipose tissue, and peripheral blood. MSCs can undergo in vitro expansion while preserving a relatively stable phenotype, enabling the cultivation of numerous cells suitable for clinical applications [34]. MSCs demonstrate the ability to relocate to areas of injury or inflammation and modulate both innate and adaptive immune reactions [35]. Furthermore, MSCs are recognized for their substantial involvement in tissue repair and regeneration, primarily attributed to the secretion of paracrine and endocrine signals with anti-inflammatory, anti-apoptotic, and pro-angiogenic properties [36].
The robust differentiation capacity of MSCs plays a notable role in facilitating tissue damage repair. Qian et al. demonstrated that MSCs derived from the bone marrow can mitigate AKI in rats by differentiating into cells resembling renal tubular epithelial cells [37]. In an AKI model, Li et al. observed that adipose MSCs transformed into renal tubular epithelial cells during the early stages of injury. This transformation assists in replacing necrotic cells, maintaining the integrity of the renal tubular structure, and contributing to tissue repair [38]. The effectiveness of MSC in AKI is primarily attributable to a paracrine mechanism [39]. Recent studies have also demonstrated that MSC can aid in the treatment of AKI through exosome secretion [40, 41] (Fig. 1B).
TCM can promote kidney injury repair by regulating MSCs
Musk has been used clinically as a natural TCM for thousands of years. Muscone, the chemical name for which is 3-methylcyclopentadecanone, is the main aromatic component of the natural Chinese medicinal musk. Musctone has anti-apoptotic and anti-oxidative stress properties and positively regulates the proliferation, secretion, and migration of bone marrow-derived MSC (BMSCs) to injured sites [42,43,44]. Liu et al. discovered that enhancing the bioactivity of BMSCs with muscone increased their therapeutic potential of BMSCs. These findings have important implications for the development of novel therapeutic approaches for the treatment of AKI [45].
Cordyceps is a traditional Chinese herbal medicinal plant genus. Such plants can be converted into a Bailing capsule through deep fermentation at low temperatures and their major component is cordycepic acid. Zhi-bo et al. showed that Bailing capsules combined with human amniotic MSCs can significantly improve adriamycin-induced nephrotic syndrome, and the improvement effect is significantly higher than that of human amniotic MSCs alone. Further studies have shown that Bailing capsules can promote the proliferation of human amniotic MSCs, thus achieving improved therapeutic effects [46].
Emodin, an anthraquinone derivative, is the main active component of rhubarb, and exhibits anti-inflammatory, antibacterial, immunomodulatory, and antioxidant properties. Studies have shown that emodin combined with BMSCs can improve ischemic reperfusion renal injury in rats more than BMSCs alone [47]. However, whether emodin affects BMSCs remains unclear.
The aforementioned studies focused on the treatment of renal injury using exogenous MSCs and Chinese medicine monomers. Whether Chinese medicine promotes kidney injury repair by regulating endogenous MSC has not yet been reported.
Some Chinese medicines and their active ingredients have been reported to regulate endogenous MSCs and have therapeutic effects against AKI. The relation of this treatment to the regulation of endogenous MSCremain uncler. For example, Jihong et al. reported that appropriate concentrations of Astragalus injection (0.05 g/mL), Astragalus IV injection (100 μmol/L), and Astragalus polysaccharide (1 mg/mL) can significantly promote the proliferation of BMSCs in rats [48]. These drugs have also received experimental support for AKI treatment [49,50,51,52]. Total saponins of Panax notoginseng can effectively improve myocardial remodeling after acute myocardial infarction, promote high expression of CD34 in the edge area of myocardial infarction, and promote the homing of CD34 + cells to the site of myocardial injury after acute myocardial infarction by the stem cell mobilizer G-CSF [53]. Notoginseng saponins can be used to treat or alleviate cisplatin-induced AKI [54]. Chinese herbs and active ingredients regulating MSC for the treatment of AKI are listed in Table 1.
PTC injury and repair
PTC and AKI
Sparse PTC is a major feature of the kidney after AKI and a risk factor for AKI-CKD transformation [73]. AKI caused by renal ischemia–reperfusion injury can lead to the cytoskeletal rearrangement of endothelial cells and damage their tight connections. After injury, capsase-3 is activated in the endothelial cells, inducing apoptosis, and leading to vascular thinning [74]. After the onset of AKI, pericytes release anti-angiogenic molecules such as ADAM metallopeptidase with thrombospondin type 1 motif 1(ADAMTS-1), which, along with inhibiting the downregulation of tissue metalloproteinase-3, threaten vascular stability and leads to capillary detachment [75]. In addition to ischemic AKI, sparse PTC has been observed in toxic and obstructed AKI/CKD models [76, 77]. The signaling pathways that trigger PTC sparring are activated early after AKI and are notable obstacles in effective renal repair and recovery [75].
Promoting PTC regeneration can promote AKI repair
Previous studies have shown that renal tubule cells promote PTC proliferation by secreting extracellular vesicles containing VEGF-A, whereas the addition of exogenous extracellular vesicles containing VEGF-A can promote PTC proliferation and kidney injury repair in ischemic AKI models [78]. BMSC transplantation can treat ischemic AKI, and its primary mechanism is to promote the repair of kidney injury by repairing PTC and increasing the PTC density [79]. Additionally, the activation of the angiopoietin-Tie2 signal through the regulation of endothelium-specific signaling pathways plays a protective effect in kidney injury caused by ischemia [80]. TCM played an important role in the repair of PTC for the treatment of AKI, which was reviewed as followsas shown in Fig. 2.
Traditional Chinese medicine is involved in the repair mechanism of AKI by intervening in vascular regeneration
TCM promote the repair of kidney injury by promoting capillary regeneration through various mechanisms
VEGF and other pro-angiogenic factors
Zhang et al. showed that salvianolic acid A alleviates AKI caused by ischemia and reperfusion. Salvianolic acid A maintaines PTC density by promoting VEGF-A expression and alleviating kidney damage caused by hypoxia [81]. Song et al. reported that an Astragalus danggui decoction improved renal function in 5/6 nephrectomized rats. Further studies have reported that Astragalus danggui decoction promotes the regeneration of PTC and glomerular capillaries through the upregulation of VEGF, thus improving renal function [82].
Endothelial progenitor cells (EPCs)
The major components of Xuebijing injection are red peony root, Chuanxiongxiong, Salvia miltiorrhiza, safflower, and angelica, which can antagonize endotoxins, improve microcirculation, protect endothelial function, and alleviate AKI caused by endotoxins in mice [83]. Jian et al. reported that Xuebijing injection promoted the proliferation, migration, and tubule formation ability of renal microvascular endothelial cells and the expression of VEGF and fibroblast growth factor 2 (FGF2), and enhanced the repair effect of EPCs on the damage of renal microvascular endothelial cells induced by Lipopolysaccharide (LPS) [84].
Curcumin is a polyphenolic compound extracted from the rhizome of the Curcuma genus that has a wide range of pharmacologicalprosperties, including anti-inflammatory, antioxidant, and antiviral properties [85]. Qi et al. investigated the effects of curcumin pre-treatment on vascular endothelial repair and EPCs homing in the renal tissue of rats with ischemia–reperfusion-induced AKI. This study confirmed that curcumin pretreatment could promote the homing of EPCs to the kidney to repair damaged endothelial cells around the capillaries, thereby reducing renal tubule injury and alleviating ischemia–reperfusion-induced AKI [86].
Numerous TCMs or active ingredients, including Astragalus and Salvia miltiorrhiza [87, 88], promote angiogenesis, and are widely used to treat kidney injury [49,50,51] (Table 2). The topic, whether these drugs promote kidney injury repair by promoting angiogenesis requires further investigation.
Macrophages and kidney injury repair
Macrophages are crucial cellular components for the restoration of renal function, exhibiting important functions beyond their well-established proinflammatory properties. Macrophages play a pivotal role in wound healing and facilitate regeneration by bridging the gap between the initial inflammatory response and the subsequent phases of tissue regeneration and repair. However, the prolonged and persistent presence of macrophages in tissues can potentially prolong the damage phase, ultimately leading to failure of tubular repair. This failure contributes to maladaptive kidney repair and plays a role in the transition from AKI to CKD [100, 101]. Figure 3 describes the mechanism of macrophages participating in the repair of AKI, and how Chinese medicine promote the repair of kidney injury through the intervention of macrophages.
Mechanism of macrophages involved in the repair of AKI and the intervention of TCM
Mechanisms of macrophages involved in renal injury repair
Retinoid acid (RA) signaling
The RA signaling pathway plays a key role in kidney development [102], and its reactivation has an important function in the repair of kidney injury [103]. Macrophage-driven RA signaling within proximal tubular epithelial cells (PTECs) has been hypothesized to contribute to the repair of these cells. This hypothesis was supported by a study using RA signaling reporter mice, specifically RARE-hsp68-LacZ mice, which express the β-galactosidase gene under the control of the RA-responsive element. These mice showed activation of the reporter in injured PTECs within 12–24 h after injury, with persistence up to 72 h and a return to baseline levels by day 7. Further investigation revealed that locally synthesized RA inhibits proinflammatory macrophages, leading to a reduction in macrophage-dependent injury following AKI. In addition, the activation of RA signaling in the injured tubular epithelium promotes alternatively activated M2 spectrum macrophages [104].
Secreting cytokines such as IL-22
Research has shown that interstitial mononuclear cells, specifically DCs and macrophages, are the primary contributors to the secretion of IL-22. Conversely, the expression of the IL-22 receptor is exclusively shown in tubular epithelial cells in kidneys [105, 106]. When IL-22-producing cells are depleted during the healing phase, they negatively affect epithelial recovery. However, in a recent study, this impairment was completely reversed when mice were reconstituted with IL-22 [107]. Another study demonstrated that IL-22 protected against ischemic AKI. Transgenic animals with IL-22 exhibited significantly higher survival rates, whereas knockout mice had a heightened mortality rate compared to wild-type (WT) mice [108].
Lipocalin-2 (Lcn-2) secretion
Macrophages promote the regeneration of renal tubular epithelial cells after kidney injury in mice by secreting Lcn-2 [109]. Brown Norway rats exhibited endogenous resistance to ischemia-induced kidney damage.Conversely, Sprague–Dawley (SD) rats showe a higher susceptibility to ischemic injury. Tolerant macrophages of Brown Norway rats express significantly higher levels of Lcn-2. In vivo studies have shown that after Lcn-2 knockdown in macrophages, renal tubular epithelial cell apoptosis and kidney injury in Brown Norway rats increase significantly and repair markers have decrease significantly, whereas lipocalin-2-overexpression cells have significantly decreased susceptibility in SD rats [110].
Wnt-β catenin signaling
The Wnt signaling pathway plays a key role in kidney development, and its reactivation plays an important role in tissue damage repair [17]. Macrophages within the kidney serve as both sources and recipients of WNT ligands [111]. Following injury, macrophages release WNT7B, which stimulates the repair and regeneration of interstitial and epithelial cells. In healthy adult kidneys, the canonical Wnt-β catenin pathway activity is limited to the papilla, whereas injury-induced pathway activation occurs in the cortical and medullary regions by day 5 post-injury [111].
Macrophage polarization
Macrophages exhibit notable plasticity in their ability to adapt to various environmental conditions and their function in the context of damage or repair is contingent on their specific phenotypes. M1 macrophages have been hypothesized to function as inflammatory cells that initiate kidney damage by releasing pro-inflammatory cytokines such as IL-6, TNFα, and IL-1β, whereas M2 macrophages play a crucial role in facilitating the restoration of kidney tissue[112, 113].
The M1/M2 macrophage ratio changes during AKI occurrence and development. In the immediate aftermath of injury, pro-inflammatory (classically activated M1) macrophages are recruited. These macrophages phagocytose cell debris, secrete cytotoxic molecules such as nitric oxide synthase (NOS) and reactive oxygen species (ROS), and induce mitochondrial damage and apoptosis [114]. Infiltrating cells release anti-inflammatory cytokines, including IL10 [115], IL4, and IL13 [116], to reverse the inflammatory environment and promote repair. These infiltrating cells include repair-promoting macrophages (type M2), CD4 + \CD8 + T cells, and regulatory T (Treg) cells. M2 macrophages produce arginase, an enzyme necessary to produce ornithine and polyamines, which are building blocks of the extracellular matrix architecture [117]. Macrophages may also participate in the repair of kidney injury by promoting angiogenesis and anti-inflammation [117].
TCM plays a role in the repair of AKI by regulating macrophages
In clinical studies, renal macrophages increase when AKI and the M2 macrophage marker CD163 is detected on the surface of 75% of macrophages in the early repair stage [118, 119]. Danhong injection alleviates AKI caused by ischemic reperfusion, partly by reducing macrophage infiltration [120]. Chen et al. showed that resveratrol can alleviate LPS-induced AKI, mainly through inhibiting the release of inflammatory factors by macrophages and the activation of TLR4 [121]. Yan et al. determined that rhabdosin alleviates AKI caused by ischemia/reperfusion. Its mechanism primarily involves the inhibition of the inflammatory response of macrophages by inhibiting the AKT signaling pathway [122]. Weijia et al. reported that astragaloside can reduce the M1 polarization of macrophages, levels of inflammatory factors IL-6 and TNF-α, and macrophage activity, thus playing a role in slowing down the kidney damage of aristolochic acid. This mechanism may be related to the partial inhibition of p38 MAPK signaling activity [123].
In the aforementioned studies, TCM played an anti-inflammatory role by reducing injury and promoting injury repair.
Regulating the balance of M1/M2 macrophage polarization may be an effective therapeutic target in AKI
Several studies have shown that regulating of macrophage M2 polarization can promote the repair of kidney injury after AKI. As mentioned, local synthesis of RA inhibits the activation of proinflammatory macrophages, leading to a decrease in macrophage-mediated damage following AKI. Additionally, RA signaling is stimulated in the injured tubular epithelium, thereby facilitating the development of alternatively activated M2 spectrum macrophages [104]. The efficacy of EPO in mitigating kidney injury has been demonstrated through its ability to decrease macrophage recruitment and facilitate the transition from M1 to M2 macrophages in vivo [124]. Furthermore, in vitro studies revealed that EPO directly inhibits the proinflammatory response of M1 macrophages and enhances the expression of M2 markers [124].
Several studies have shown that berberine promotes the transformation of macrophages into M2 macrophages. Yang et al. showed that in chronic atrophic gastritis induced by Helicobacter pylori, berberine regulates macrophage polarization through the IL-4-STAT6 signaling pathway, inhibits the M1 type, and promotes M2 type transformation [125]. Similar results were observed in a mouse model of ulcerative colitis [126]. Lin et al. reported that berberine reduced adipose tissue inflammation in mice fed a high-fat diet. This promotes the transformation of macrophages into the M2 type [127]. Gao et al. reported that curcumin promotes the secretion of IL4 and or IL13 by macrophages and the polarization of M2 macrophages in experimental autoimmune myocarditis models [128]. In addition, the active ingredients in Chinese medicines, such as astragaloside, diosgenin, ginsenoside Rg1, Lupeol, and Platycodin D, promote the polarization of M2 macrophages [129,130,131,132,133]. However, whether berberine [134], curcumin [85], astragaloside [49,50,51], diosgenin [135], and ginsenoside Rg1 [58] used in the treatment of AKI (Table 3) are related to the promotion of polarization of M2 macrophages requires further study.
Conclusions and perspectives
The use of drugs and therapies to mobilize the body’s own ability to eliminate disease and restore health is a primary feature of TCM. Several human organs and tissues exhibit varying degrees of regenerative potential, which can be activated under certain conditions and play a role in treating diseases. In the past, the kidneys were assumed to have no regenerative capacity. However, with progress in science and technology, increasing evidence has shown that the kidney has a certain regenerative ability, especially in the repair process of AKI [3, 4]. TCM scholars assume that Jing is fundamental for human development, regeneration, repair and maintenance of life. Jing has a similar role and status to stem cells in regenerative medicine. When the kidney injury is relatively serious, an imbalance occurs between the kidney injury and the regenerative ability, which requires drug intervention. An increasing number of studies have shown that TCM plays an important role in the treatment of AKI [31,32,33]. However, most studies have focused on the protective effects of Chinese herbs or monomers against kidney damage, and the mechanisms typically include the inhibition of apoptosis as well as anti-inflammatory and antioxidant effects. Such research predominantly highlights the perspectives of TCM that involves eliminating disease-causing factors, while overlooking its crucial role in strengthening the body’s natural defenses, thus failing to capture the holistic essence of TCM..
In this study, we discussed the mechanisms of TCM in renal tubule regeneration, microvascular regeneration, and immune cell regulation in renal injury, staring from the mechanism of renal regeneration. Renal tubule injury is the primary feature of AKI and repairing this damage is central to the treatment of AKI. Promoting the proliferation and differentiation of renal progenitor cells and activating MSCs are key to promoting renal tubule regeneration and repair. Recent studies have found that 7-HC and isoflavin can promote the regeneration and repair of renal tubules [31, 32]. Other drugs that can promote the Sox9\CD133\WNT signaling pathway or activate MSCs (Table 1) may also play a role in the treatment of AKI; however, further investigation is required.
Micro vessel thinning is another characteristic of AKI and is closely related to prognosis. Recent studies have confirmed that the Chinese herbal compounds Astragalus danggui decoction, Xuebijing, traditional Chinese monomer salvianolic acid A, and curcumin can promote kidney injury repair by promoting vascular regeneration[81,82,83, 86].Other studies have reported that several microvascular regeneration drugs (Table 2) may also be effective in the treatment of AKI; therefore, further studies are required.
Macrophages play an indispensable role in the repair of renal injury. Studies on the influence of TCM on the prognosis of AKI by macrophage intervention have focused on the inhibition of macrophage infiltration or the reduction of macrophages. The regulation of macrophage M2 polarization promotes the repair of kidney injury after AKI [104, 122]. Currently, no reports are available, on the use of TCM or its active ingredients to interfere with macrophage M2 polarization and promote AKI repair, which may thus be the required direction of future research.
In conclusion, starting from the mobilization of the regenerative potential of the kidneys, this study discusses the research progress on TCM in the regulation the damage repair of renal tubular epithelial cells, damage repair of PTC, and immunity by TCM and presents insights to provide research foundations in this field.
Availability of data and materials
No data was used for the research described in the article.
References
Zarbock A, Forni LG, Ostermann M, Ronco C, Bagshaw SM, Mehta RL, et al. Designing acute kidney injury clinical trials. Nat Rev Nephrol. 2024;2024(20):137–46. https://doi.org/10.1038/s41581-023-00758-1.
Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and ckd. Nat Rev Nephrol. 2015;11:264–76. https://doi.org/10.1038/nrneph.2015.3.
Lazzeri E, Angelotti ML, Peired A, Conte C, Marschner JA, Maggi L, et al. Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury. Nat Commun. 2018;9:1344. https://doi.org/10.1038/s41467-018-03753-4.
Kumar S, Liu J, Pang P, Krautzberger AM, Reginensi A, Akiyama H, et al. Sox9 activation highlights a cellular pathway of renal repair in the acutely injured mammalian kidney. Cell Rep. 2015;12:1325–38. https://doi.org/10.1016/j.celrep.2015.07.034.
Han Q, Wang X, Ding X, He J, Cai G, Zhu H. Immunomodulatory effects of mesenchymal stem cells on drug-induced acute kidney injury. Front Immunol. 2021;12: 683003. https://doi.org/10.3389/fimmu.2021.683003.
Bassi EJ, De-Almeida DC, Moraes-Vieira PM, et al. Exploring the role of soluble factors associated with immune regulatory properties of mesenchymal stem cells. Stem Cell Rev Rep. 2012;8:329–42. https://doi.org/10.1007/s12015-011-9311-1.
Au P, Tam J, Fukumura D, Jain RK. Bone marrow-derived mesenchymal stem. Leukemia Lymphoma. 2005;46:4551–8. https://doi.org/10.1182/blood-2007-10-118273.
Lan S, Yang B, Migneault F, Turgeon J, Bourgault M, Dieudé M, et al. Caspase-3-dependent peritubular capillary dysfunction is pivotal for the transition from acute to chronic kidney disease after acute ischemia–reperfusion injury. Am J Physiol Renal Physiol. 2021;321:F335–51. https://doi.org/10.1152/ajprenal.00690.2020.
Jang HR, Rabb H. Immune cells in experimental acute kidney injury. Nat Rev Nephrol. 2015;11:88–101. https://doi.org/10.1038/nrneph.2014.180.
Bonavia A, Singbartl K. A review of the role of immune cells in acute kidney injury. Pediatr Nephrol. 2018;33:1629–39. https://doi.org/10.1007/s00467-017-3774-5.
Oliver J. The histogenesis of chronic uranium nephritis with especial reference to epithelial regeneration. J Exp Med. 1915;21:425–50. https://doi.org/10.1084/jem.21.5.425.
Chang-Panesso M, Kadyrov FF, Lalli M, Wu H, Ikeda S, Kefaloyianni E, et al. Foxm1 drives proximal tubule proliferation during repair from acute ischemic kidney injury. J Clin Investig. 2019;129:5501–17. https://doi.org/10.1172/JCI125519.
Humphreys BD, Czerniak S, DiRocco DP, Hasnain W, Cheema R, Bonventre JV, et al. Repair of injured proximal tubule does not involve specialized progenitors. Proc Natl Acad Sci USA. 2011;108:9226–31. https://doi.org/10.1073/pnas.1100629108.
Kusaba T, Lalli M, Kramann R, et al. Differentiated kidney epithelial cells repair injured proximal tubule. Proc Nat Acad Sci. 2014;111:1527–32. https://doi.org/10.1073/pnas.1310653110.
Chang-Panesso M, Humphreys BD. Cellular plasticity in kidney injury and repair. Nat Rev Nephrol. 2017;13:39–46. https://doi.org/10.1038/nrneph.2016.169.
Berger K, Bangen JM, Hammerich L, Liedtke C, Floege J, Smeets B, et al. Origin of regenerating tubular cells after acute kidney injury. Proc Nat Acad Sci. 2014;111:1533–8. https://doi.org/10.1073/pnas.1316177111.
Schunk SJ, Floege J, Fliser D, Speer T. Wnt-beta-catenin signaling—a versatile player in kidney injury and repair. Nat Rev Nephrol. 2021;17:172–84. https://doi.org/10.1038/s41581-020-00343-w.
Brossa A, Papadimitriou E, Collino F, Incarnato D, Oliviero S, Camussi G, et al. Role of cd133 molecule in wnt response and renal repair. Stem Cells Transl Med. 2018;7:283–94. https://doi.org/10.1002/sctm.17-0158.
Kang HM, Huang S, Reidy K, Han SH, Chinga F, Susztak K. Sox9-positive progenitor cells play a key role in renal tubule epithelial regeneration in mice. Cell Rep. 2016;14:861–71. https://doi.org/10.1016/j.celrep.2015.12.071.
Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, et al. Isolation and characterization of multipotent progenitor cells from the bowman’s capsule of adult human kidneys. J Am Soc Nephrol. 2006;17:2443–56. https://doi.org/10.1681/ASN.2006010089.
Nie H, Zhao Z, Zhou D, Li D, Wang Y, Ma Y, et al. Activated sox9+ renal epithelial cells promote kidney repair through secreting factors. Cell Prolif. 2023;56:e13394. https://doi.org/10.1111/cpr.13394.
Ma Q, Wang Y, Zhang T, Zuo W. Notch-mediated sox9 cell activation contributes to kidney repair after partial nephrectomy. Life Sci. 2018;193:104–9. https://doi.org/10.1016/j.lfs.2017.11.041.
Dreval K, de Conti A, Furuya S, Beland FA, Rusyn I, Pogribny IP. Mir-1247 blocks sox9-mediated regeneration in alcohol- and fibrosis-associated acute kidney injury in mice. Toxicology. 2017;384:40–9. https://doi.org/10.1016/j.tox.2017.03.004.
Grange C, Moggio A, Tapparo M, Porta S, Camussi G, Bussolati B. Protective effect and localization by optical imaging of human renal cd133+ progenitor cells in an acute kidney injury model. Physiol Rep. 2014;2: e12009. https://doi.org/10.14814/phy2.12009.
Hoshina A, Kawamoto T, Sueta SI, Mae SI, Araoka T, Tanaka H, et al. Development of new method to enrich human ipsc-derived renal progenitors using cell surface markers. Sci Rep. 2018;8:6375. https://doi.org/10.1038/s41598-018-24714-3.
Kim JY, Bai Y, Jayne LA, Hector RD, Persaud AK, Ong SS, et al. A kinome-wide screen identifies a cdkl5-sox9 regulatory axis in epithelial cell death and kidney injury. Nat Commun. 2020;11:1915–24. https://doi.org/10.1038/s41467-020-15638-6.
Kim JY, Silvaroli JA, Martinez GV, Bisunke B, Luna Ramirez AV, Jayne LA, et al. Zinc finger protein 24-dependent transcription factor sox9 up-regulation protects tubular epithelial cells during acute kidney injury. Kidney Int. 2023;103:1093–104. https://doi.org/10.1016/j.kint.2023.02.026.
Ohnishi S, Maehara O, Nakagawa K, Kameya A, Otaki K, Fujita H, et al. Hypoxia-inducible factors activate CD133 promoter through ets family transcription factors. PLoS ONE. 2013;8: e66255. https://doi.org/10.1371/journal.pone.0066255.
Bussolati B, Moggio A, Collino F, Aghemo G, D’Armento G, Grange C, et al. Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+ progenitors through oct4/mir-145 balance. Am J Physiol Renal Physiol. 2012;302:F116–28. https://doi.org/10.1152/ajprenal.00184.2011.
Maehara O, Ohnishi S, Asano A, Suda G, Natsuizaka M, et al. Metformin regulates the expression of cd133 through the ampk-cebpβ pathway in hepatocellular carcinoma cell lines. Neoplasia. 2019;21:545–56. https://doi.org/10.1016/j.neo.2019.03.007.
Wu WF, Wang JN, Li Z, Wei B, Jin J, Gao L, et al. 7-hydroxycoumarin protects against cisplatin-induced acute kidney injury by inhibiting necroptosis and promoting sox9-mediated tubular epithelial cell proliferation. Phytomedicine. 2020;69: 153202. https://doi.org/10.1016/j.phymed.2020.153202.
Zheng Q, Zhang Y, Wang X, Wang F, Zhao H. Isorhapontigenin modulates sox9/tollip expression to attenuate cell apoptosis and oxidative stress in paraquat-induced acute kidney injury. Oxid Med Cell Longev. 2022;9:3328623. https://doi.org/10.1155/2022/3328623.
Huang Z, He L, Huang D, Lei S, Gao J. Icariin protects rats against 5/6 nephrectomy-induced chronic kidney failure by increasing the number of renal stem cells. BMC Complement Altern Med. 2015;15:378. https://doi.org/10.1186/s12906-015-0909-8.
Haack-Sørensen M, Hansen SK, Hansen L, Gaster M, Hyttel P, Ekblond A, et al. Mesenchymal stromal cell phenotype is not influenced by confluence during culture expansion. Stem Cell Rev. 2013;9:44–58. https://doi.org/10.1007/s12015-012-9386-3.
Le-Blanc K, Davies LC. Mesenchymal stromal cells and the innate immune response. Immunol Lett. 2015;168:140–6. https://doi.org/10.1016/j.imlet.2015.05.004.
Akasaka Y. The role of mesenchymal dtromal cells in tissue repair and fibrosis. Adv Wound Care. 2022;11:561–74. https://doi.org/10.1089/wound.2021.0037.
Qian H, Yang H, Xu W, Yan Y, Chen Q, Zhu W, et al. Bone marrow mesenchymal stem cells ameliorate rat acute renal failure by differentiation into renal tubular epithelial-like cells. Int J Mol Med. 2008;22:325–32. https://doi.org/10.3892/ijmm_00000026.
Li K, Han Q, Yan X, Liao L, Zhao RC. Not a process of simple vicariousness, the differentiation of human adipose-derived mesenchymal stem cells to renal tubular epithelial cells plays an important role in acute kidney injury repairing. Stem Cells Dev. 2010;19:1267–75. https://doi.org/10.1089/scd.2009.0196.
Birtwistle L, Chen XM, Pollock C. Mesenchymal stem cell-derived extracellular vesicles to the rescue of renal injury. Int J Mol Sci. 2021;22:6596. https://doi.org/10.3390/ijms22126596.
Huang J, Cao H, Cui B, Ma X, Gao L, Yu C, et al. Mesenchymal stem cells-derived exosomes ameliorate ischemia/reperfusion induced acute kidney injury in a porcine model. Front Cell Dev Biol. 2022;10: 899869. https://doi.org/10.3389/fcell.2022.899869.
Cao J, Wang B, Tang T, Lv L, Ding Z, Li Z, et al. Three-dimensional culture of mscs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury. Stem Cell Res Ther. 2020;11:206. https://doi.org/10.1186/s13287-020-01719-2.
Hou FY, Xie XW, Xi FQ, Xu SH, Li SH, Song M. Effects of muscone-containing serum on proliferation and differentiation of rat mesenchymal stem cells. J Xi’an Jiao tong Univ. 2013;34:110–4. https://doi.org/10.1371/journal.pone.0097123.
Liu MJ, Liu PF, Zhao L. Effect analysis of muscone on the osteogenic potential of rat bone marrow derived mesenchymal stem cells. Chin J Lab Diagn. 2015;10:1618–21.
Xie XW, Hou FW, Li N. Effects of musk ketone at different concentrations on in vivo migration of exogenous rat bone marrow mesenchymal stem cells. Chin J Integr Tradit West Med. 2012;32:980–5. https://doi.org/10.7661/CJIM.2012.7.980.
Liu P, Feng Y, Dong C, Yang D, Li B, Chen X, et al. Administration of BMSCS with muscone in rats with gentamicin-induced aki improves their therapeutic efficacy. PLoS ONE. 2014;9: e97123. https://doi.org/10.1371/journal.pone.0097123.
Guo ZB, Zhang CJ, Ma LN, Gao DW, Zhou F, Li NN, et al. Effect of corbrin capsule combined with human amniotic mesenchymal stem cell transplantation on rat renal function and hypercoagulability. Chin J Tissue Eng Res. 2017;21:133–9. https://doi.org/10.3969/j.issn.2095-4344.2017.01.024.
Li Z. Emodin effects on renal ischemia/reperfusion injury after bone marrow mesenchymal stem cell transplantation. Chin J Tissue Eng Res. 2016;20:2052–8. https://doi.org/10.3969/j.issn.2095-4344.2016.14.011.
Hou JH, Lu J, Zhao Y, Jin LM, Yan L, Jia J, et al. Effect of Huangqi injection, astragaloside and astragalan on proliferation of rat bone marrow mesenchymal stem cells. Lishizhen Med Mater Med Res. 2016;27:1070–2. https://doi.org/10.3969/j.issn.1008-0805.
Su Y, Xu J, Chen S, Feng J, Li J, Lei Z, et al. Astragaloside iv protects against ischemia/reperfusion (i/r)-induced kidney injury based on the keap1-nrf2/are signaling pathway. Transl Androl Urol. 2022;11:1177–88. https://doi.org/10.21037/tau-22-505.
Zhou W, Chen Y, Zhang X. Astragaloside iv alleviates lipopolysaccharide-induced acute kidney injury through down-regulating cytokines, ccr5 and p-erk, and elevating anti-oxidative ability. Med Sci Monit. 2017;23:1413–20. https://doi.org/10.12659/msm.899618.
Yan W, Xu Y, Yuan Y, Tian L, Wang Q, Xie Y, et al. Renoprotective mechanisms of astragaloside iv in cisplatin-induced acute kidney injury. Free Radic Res. 2017;51:669–83. https://doi.org/10.1080/10715762.2017.1361532.
Sun J, Wei S, Zhang Y, Li J. Protective effects of astragalus polysaccharide on sepsis-induced acute kidney injury. Anal Cell Pathol. 2021;2021:7178253. https://doi.org/10.1155/2021/7178253.
Zhao HB, Zhang XJ, Wang S, Guo M, Ma D, Xu XY. Effect of placing on home of BMSCs in myocardial remodeling after AMI and effect of activating blood circulation and removing stasis. J Tianjin Univ Tradit Chin Med. 2013;32:28–31.
Li Q, Zhang Y, Yang Y, Huang S, Zou X, Wei C, et al. Panax notoginseng saponins reduces the cisplatin-induced acute renal injury by increasing hif-1α/bnip3 to inhibit mitochondrial apoptosis pathway. Biomed Pharmacother. 2021;142: 111965. https://doi.org/10.1016/j.biopha.2021.111965.
Xie C, Liu L, Wang Z, Xie H, Feng Y, Suo J, et al. Icariin improves sepsis-induced mortality and acute kidney injury. Pharmacology. 2018;102:196–205. https://doi.org/10.1159/000487955.
Li X, Wen Y, Sheng L, Guo R, Zhang Y, Shao L. Icariin activates autophagy to trigger tgfbeta1 upregulation and promote angiogenesis in ea.hy926 human vascular endothelial cells. Bioengineered. 2022;13:164–77. https://doi.org/10.1080/21655979.2021.2011637.
Li L, Zheng HL, Kou Y, Zhang J, Yang HY. Study on the osteogenic differentiation of rabbit bone marrow mesenchymal stem cell induced by icariin. CJTCMP. 2018;36:2599–601.
Guo J, Wang R, Min F. Ginsenoside rg1 ameliorates sepsis-induced acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells. J Leukoc Biol. 2022;112:1065–77. https://doi.org/10.1002/JLB.1A0422-211R.
Luo Y, Wang B, Liu J, Ma F, Luo D, Zheng Z, et al. Ginsenoside rg1 enhances the paracrine effects of bone marrow-derived mesenchymal stem cells on radiation induced intestinal injury. Aging. 2021;13:1132–52. https://doi.org/10.18632/aging.202241.
Kaur A, Kaur T, Singh B, Pathak D, Singh Buttar H, Pal SA. Curcumin alleviates ischemia reperfusion-induced acute kidney injury through nmda receptor antagonism in rats. Ren Fail. 2016;38:1462–7. https://doi.org/10.1080/0886022X.2016.1214892.
Huang W, Li X, Wang D, Sun Y, Wang Q, Bu Y, et al. Curcumin reduces lps-induced septic acute kidney injury through suppression of lncrna pvt1 in mice. Life Sci. 2020;254: 117340. https://doi.org/10.1016/j.lfs.2020.117340.
Wu J, Pan X, Fu H, Zheng Y, Dai Y, Yin Y, et al. Effect of curcumin on glycerol-induced acute kidney injury in rats. Sci Rep. 2017;7:10114. https://doi.org/10.1038/s41598-017-10693-4.
Lan T, Guo H, Lu X, Geng K, Wu L, Luo Y, et al. Dual-responsive curcumin-loaded nanoparticles for the treatment of cisplatin-induced acute kidney injury. Biomacromol. 2022;23:5253–66. https://doi.org/10.1021/acs.biomac.2c01083.
He X, Zhang C, Amirsaadat S, Jalil AT, Kadhim MM, Abasi M, et al. Curcumin-loaded mesenchymal stem cell-derived exosomes efficiently attenuate proliferation and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Appl Biochem Biotechnol. 2023;195:51–67. https://doi.org/10.1007/s12010-022-04090-5.
Zhang JS, He QY, Huang T, Zhang BX. Effects of panax notoginseng saponins on homing of c-kit+ bone mesenchymal stem cells to the infarction heart in rats. J Tradit Chin Med. 2011;31:203–8. https://doi.org/10.1016/s0254-6272(11)60043-5.
Ying J, Wu J, Zhang Y, Han Y, Qian X, Yang Q, et al. Ligustrazine suppresses renal nmdar1 and caspase-3 expressions in a mouse model of sepsis-associated acute kidney injury. Mol Cell Biochem. 2020;464:73–81. https://doi.org/10.1007/s11010-019-03650-4.
Jiang G, Xin R, Yuan W, Zhang L, Meng X, Sun W, et al. Ligustrazine ameliorates acute kidney injury through downregulation of nod2-mediated inflammation. Int J Mol Med. 2020;45:731–42. https://doi.org/10.3892/ijmm.2020.4464.
Cao H, Zhu X, Zhang J, Xu M, Ge L, Zhang C. Dose-dependent effects of tetramethylpyrazine on the characteristics of human umbilical cord mesenchymal stem cells for stroke therapy. Neurosci Lett. 2020;722: 134797. https://doi.org/10.1016/j.neulet.2020.134797.
Wang B, Wang Y, Xu K, Zeng Z, Xu Z, Yue D, et al. Resveratrol alleviates sepsis-induced acute kidney injury by deactivating the lncrna malat1/mir-205 axis. Cent Eur J Immunol. 2021;46:295–304. https://doi.org/10.5114/ceji.2021.109195.
Lei LT, Chen JB, Zhao YL, Yang SP, He L. Resveratrol attenuates senescence of adipose-derived mesenchymal stem cells and restores their paracrine effects on promoting insulin secretion of ins-1 cells through pim-1. Eur Rev Med Pharmacol Sci. 2016;20:1203–13.
Mu L, Hu G, Liu J, Chen Y, Cui W, Qiao L. Protective effects of naringenin in a rat model of sepsis-triggered acute kidney injury via activation of antioxidant enzymes and reduction in urinary angiotensinogen. Med Sci Monit. 2019;25:5986–91. https://doi.org/10.12659/MSM.916400.
Wu YT, Liu HL. Effect of naringenin on proliferation of adipose-derived stem cell. J Tongji Univ. 2021;42:3–10. https://doi.org/10.12289/j.issn.1008-0392.20367.
Kramann R, Tanaka M, Humphreys BD. Fluorescence microangiography for quantitative assessment of peritubular capillary changes after aki in mice. J Am Soc Nephrol. 2014;25:1924–31. https://doi.org/10.1681/ASN.2013101121.
Yang B, Lan S, Dieudé M, Sabo-Vatasescu JP, Karakeussian-Rimbaud A, Turgeon J, et al. Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J Am Soc Nephrol. 2018;29:1900–16. https://doi.org/10.1681/ASN.2017050581.
Kumar S. Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int. 2018;93:27–40. https://doi.org/10.1016/j.kint.2017.07.030.
Miao C, Zhu X, Wei X, Long M, Jiang L, Li C, et al. Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases. Ren Fail. 2022;44:881–92. https://doi.org/10.1080/0886022X.2022.2079528.
Tanimura S, Tanabe K, Miyake H, Masuda K, Tsushida K, Morioka T, et al. Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model. Am J Physiol Renal Physiol. 2019;317:F264–74. https://doi.org/10.1152/ajprenal.00045.2019.
Zhong X, Tang TT, Shen AR, Cao JY, Jing J, Wang C, et al. Tubular epithelial cells-derived small extracellular vesicle-vegf-a promotes peritubular capillary repair in ischemic kidney injury. NPJ Regen Med. 2022;7:73. https://doi.org/10.1038/s41536-022-00268-x.
Hu W, Li Z, Li H, Pan W, Cheng J, Zhao S, et al. Bone marrow-derived mesenchymal stem cells transplantation attenuates renal fibrosis following acute kidney injury by repairing the peritubular capillaries. Exp Cell Res. 2022;411: 112983. https://doi.org/10.1016/j.yexcr.2021.112983.
Li Y, Liu P, Zhou Y, Maekawa H, Silva JB, Ansari MJ, et al. Activation of angiopoietin-tie2 signaling protects the kidney from ischemic injury by modulation of endothelial-specific pathways. J Am Soc Nephrol. 2023;34:969–87. https://doi.org/10.1681/ASN.0000000000000098.
Zhang Z, Qi D, Wang X, Gao Z, Li P, Liu W, et al. Protective effect of salvianolic acid a on ischaemia-reperfusion acute kidney injury in rats through protecting against peritubular capillary endothelium damages. Phytother Res. 2018;32:103–14. https://doi.org/10.1002/ptr.5954.
Song J, Meng L, Li S, Qu L, Li X. A combination of chinese herbs, astragalus membranaceus var. Mongholicus and angelica sinensis, improved renal microvascular insufficiency in 5/6 nephrectomized rats. Vascul Pharmacol. 2009;50:185–93. https://doi.org/10.1016/j.vph.2009.01.005.
Liu J, Wang Z, Lin J, Li T, Guo X, Pang R, et al. Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders and suppresses activation of local inflammation. J Ethnopharmacol. 2021;276: 114199. https://doi.org/10.1016/j.jep.2021.114199.
Zhuo J, Zheng WP, Wen JH, Wu YC, Chen S. Role and mechanism of Xuebijing injection in the repair of lipopolysaccharide-induced renal endothelial cell injury by endothelial progenitor cells. Modern J Integr Tradit Chin Western Med. 2021;30(2533–2539):2595. https://doi.org/10.3969/j.issn.1008-8849.2021.23.006.
Kotha RR, Luthria DL. Curcumin: biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules. 2019;24:1930. https://doi.org/10.3390/molecules24162930.
Ni Q, Lin H. Effect of preconditioning with curcumin on vascular endothelium repair and endothelial progenitor cell homing in renal tissues of rats with acute kidney injury induced by ischemia-reperfusion. Guangxi Med J. 2021;43:2699–703. https://doi.org/10.11675/j.issn.0253-4304.2021.22.13.
Sui YB, Wang Y, Liu L, Liu F, Zhang YQ. Astragaloside iv alleviates heart failure by promoting angiogenesis through the jak-stat3 pathway. Pharm Biol. 2019;57:48–54. https://doi.org/10.1080/13880209.2019.1569697.
Zhang G, Huang J, Hao S, Zhang J, Zhou N. Radix astragalus polysaccharide accelerates angiogenesis by activating akt/enos to promote nerve regeneration and functional recovery. Front Pharmacol. 2022;13: 838647. https://doi.org/10.3389/fphar.2022.838647.
Yu LJ, Zhang KJ, Zhu JZ, Zheng Q, Bao XY, Thapa S, et al. Salvianolic acid exerts cardioprotection through promoting angiogenesis in animal models of acute myocardial infarction: preclinical evidence. Oxid Med Cell Longev. 2017;2017:1–11. https://doi.org/10.1155/2017/8192383.
Pang Y, Zhang PC, Lu RR, Li HL, Li JC, Fu HX, et al. Andrade-oliveira salvianolic acid b modulates caspase-1-mediated pyroptosis in renal ischemia-reperfusion injury via nrf2 pathway. Front Pharmacol. 2020;11: 541426. https://doi.org/10.3389/fphar.2020.541426.
Chen J, Wang Y, Wang S, Zhao X, Zhao L, Wang Y. Salvianolic acid b and ferulic acid synergistically promote angiogenesis in huvecs and zebrafish via regulating VEGF signaling. J Ethnopharmacol. 2022;283: 114667. https://doi.org/10.1016/j.jep.2021.114667.
Fan H, Su BJ, Le JW, Zhu JH. Salidroside protects acute kidney injury in septic rats by inhibiting inflammation and apoptosis. Drug Des Devel Ther. 2022;16:899–907. https://doi.org/10.2147/DDDT.S361972.
Guo Q, Yang J, Chen Y, Jin X, Li Z, Wen X. Salidroside improves angiogenesis-osteogenesis coupling by regulating the hif-1α/VEGF signalling pathway in the bone environment. Eur J Pharmacol. 2020;884: 173394. https://doi.org/10.1016/j.ejphar.2020.173394.
Wu Z, Li C, Li Q, Li J, Lu X. Puerarin alleviates cisplatin-induced acute renal damage and upregulates microrna-31-related signaling. Exp Ther Med. 2020;20:3122–9. https://doi.org/10.3892/etm.2020.9081.
Liu X, Sui X, Zhang Y, Yue R, Yin S. Efficacy of puerarin in rats with focal cerebral ischemia through modulation of the SIRT1/HIF-1α/VEGF signaling pathway and its effect on synaptic plasticity. Heliyon. 2023;9: e15872. https://doi.org/10.1016/j.heliyon.2023.e15872.
Chen J, Zhang X, Liu X, Zhang C, Shang W, Xue J, et al. Ginsenoside rg1 promotes cerebral angiogenesis via the pi3k/akt/mtor signaling pathway in ischemic mice. Eur J Pharmacol. 2019;856: 172418. https://doi.org/10.1016/j.ejphar.2019.172418.
Ma P, Zhang S, Su X, Qiu G, Wu Z. Protective effects of icariin on cisplatin-induced acute renal injury in mice. Am J Transl Res. 2015;7:2105–14.
Zhong J, Lu W, Zhang J, Huang M, Lyu W, Ye G, et al. Notoginsenoside R1 activates the ang2/tie2 pathway to promote angiogenesis. Phytomedicine. 2020;78: 153302. https://doi.org/10.1016/j.phymed.2020.153302.
Liu WJ, Tang HT, Jia YT, Ma B, Fu JF, Wang Y, et al. Notoginsenoside R1 attenuates renal ischemia-reperfusion injury in rats. Shock. 2010;34:314–20. https://doi.org/10.12659/MSM.920442.
DeWolf SE, Kasimsetty SG, Hawkes AA, Stocks LM, Kurian SM, McKay DB. Damps released from injured renal tubular epithelial cells activate innate immune signals in healthy renal tubular epithelial cells. Transplantation. 2022;106:1589–99. https://doi.org/10.1097/TP.0000000000004038.
Habib R. Multifaceted roles of toll-like receptors in acute kidney injury. Heliyon. 2021;7: e06441. https://doi.org/10.1016/j.heliyon.2021.e06441.
Rosselot C, Spraggon L, Chia I, Batourina E, Riccio P, Lu B, et al. Non-cell-autonomous retinoid signaling is crucial for renal development. Development. 2010;137:283–92. https://doi.org/10.1242/dev.040287.
Perez A, Ramirez-Ramos M, Calleja C, Martin D, Namorado MC, Sierra G, et al. Beneficial effect of retinoic acid on the outcome of experimental acute renal failure. Nephrol Dial Transplant. 2004;19:2464–71. https://doi.org/10.1093/ndt/gfh400.
Chiba T, Skrypnyk NI, Skvarca LB, Penchev R, Zhang KX, Rochon ER, et al. Retinoic acid signaling coordinates macrophage-dependent injury and repair after AKI. J Am Soc Nephrol. 2016;27:495–508. https://doi.org/10.1681/ASN.2014111108.
Kulkarni OP, Hartter I, Mulay SR, Hagemann J, Darisipudi MN, Kumar Vr S, et al. Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. J Am Soc Nephrol. 2014;25(5):978–89. https://doi.org/10.1681/ASN.2013050528.
Chen W, Shen Y, Fan J, Zeng X, Zhang X, Luan J, et al. IL-22-mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury. Clin Transl Med. 2021;11(2): e324. https://doi.org/10.1002/ctm2.324.
Kulkarni OP, Hartter I, Mulay SR, Hagemann J, Darisipudi MN, Kumar Vr S, et al. Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. J Am Soc Nephrol. 2014;25:978–89. https://doi.org/10.1681/ASN.2013050528.
Xu MJ, Feng D, Wang H, Guan Y, Yan X, Gao B. IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium. J Am Soc Nephrol. 2014;25:967–77. https://doi.org/10.1681/ASN.2013060611.
Weigert A, Olesch C, Brune B. Sphingosine-1-phosphate and macrophage biology—how the sphinx tames the big eater. Front Immunol. 2019;10:1706. https://doi.org/10.3389/fimmu.2019.01706.
Jung M, Brüne B, Hotter G, Sola A. Macrophage-derived lipocalin-2 contributes to ischemic resistance mechanisms by protecting from renal injury. Sci Rep. 2016;6:21950. https://doi.org/10.1038/srep21950.
Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, et al. Macrophage wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci. 2010;107:4194–9. https://doi.org/10.1073/pnas.0912228107.
Desgeorges T, Caratti G, Mounier R, Tuckermann J, Chazaud B. Glucocorticoids shape macrophage phenotype for tissue repair. Front Immunol. 2019;10:1591. https://doi.org/10.3389/fimmu.2019.01591.
Lech M, Gröbmayr R, Ryu MI, Lorenz G, Hartter I, Mulay SR, et al. Macrophage phenotype controls long-term aki outcomes-kidney regeneration versus atrophy. J Am Soc Nephrol. 2014;25:292–304. https://doi.org/10.1681/ASN.2013020152.
Gottlieb RA. Cell death pathways in acute ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther. 2011;16:233–8. https://doi.org/10.1177/1074248411409581.
Wei W, Zhao Y, Zhang Y, Jin H, Shou S. The role of il-10 in kidney disease. Int Immunopharmacol. 2022;108: 108917. https://doi.org/10.1016/j.intimp.2022.108917.
Zhang MZ, Wang X, Wang YQ, Niu AL, Harris RC. Il-4/il-13-mediated polarization of renal macrophages/dendritic cells to an m2a phenotype is essential for recovery from acute kidney injury. Kidney Int. 2017;91:375–86. https://doi.org/10.1016/j.kint.2016.08.020.
Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Cell Metab. 2012;15:432–7. https://doi.org/10.1016/j.cmet.2011.11.013.
Tanaka K, Tanabe K, Nishii N, Takiue K, Sugiyama H, Wada J. Sustained tubulointerstitial inflammation in kidney with severe leptospirosis. Intern Med. 2017;56:1179–84. https://doi.org/10.2169/internalmedicine.56.8084.
Rubio-Navarro A, Carril M, Padro D, Guerrero-Hue M, Tarín C, Samaniego R, et al. CD163-macrophages are involved in rhabdomyolysis-induced kidney injury and may be detected by mri with targeted gold-coated iron oxide nanoparticles. Theranostics. 2016;6:896–914. https://doi.org/10.7150/thno.14915.
Yuan SY. Protective effect and mechanism of Dan hong injection on acute kidney injury induced by ischemia reperfusion in rats. Guangdong Pharmaceut Univ. 2023. https://doi.org/10.27690/d.cnki.ggdyk.2020.000232.
Chen L, Yang S, Zumbrun EE, Guan H, Nagarkatti PS, Nagarkatti M. Resveratrol attenuates lipopolysaccharide-induced acute kidney injury by suppressing inflammation driven by macrophages. Mol Nutr Food Res. 2015;59:853–64. https://doi.org/10.1002/mnfr.201400819.
Yan Y, Tan RZ, Liu P, Li JC, Zhong X, Liao Y, et al. Oridonin alleviates IRI-induced kidney injury by inhibiting inflammatory response of macrophages via AKT-related pathways. Med Sci Monit. 2020;26: e921114. https://doi.org/10.12659/MSM.921114.
Xu WJ, Chen JJ, Yan LQ, Zhang Y, Wang LP, Zhuang YZ. Effect of astragaloside IV on aristolochic acid-induced M1-type polarization of macrophages and its mechanism study. Progr Modern Biomed. 2021;21:1040–5. https://doi.org/10.13241/j.cnki.pmb.2021.06.009.
Wang S, Zhang C, Li J, Niyazi S, Zheng L, Xu M, et al. Erythropoietin protects against rhabdomyolysis-induced acute kidney injury by modulating macrophage polarization. Cell Death Dis. 2017;8: e2725. https://doi.org/10.1038/cddis.2017.104.
Yang T, Wang R, Liu H, Wang L, Li J, Wu S, et al. Berberine regulates macrophage polarization through il-4-stat6 signaling pathway in helicobacter pylori-induced chronic atrophic gastritis. Life Sci. 2021;266: 118903. https://doi.org/10.1016/j.lfs.2020.118903.
Xiong K, Deng J, Yue T, Hu W, Zeng X, Yang T, et al. Berberine promotes m2 macrophage polarisation through the il-4-stat6 signalling pathway in ulcerative colitis treatment. Heliyon. 2023;9: e14176. https://doi.org/10.1016/j.heliyon.2023.e14176.
Lin J, Cai Q, Liang B, Wu L, Zhuang Y, He Y, et al. Berberine, a traditional chinese medicine, reduces inflammation in adipose tissue, polarizes m2 macrophages, and increases energy expenditure in mice fed a high-fat diet. Med Sci Monit. 2019;25:87–97. https://doi.org/10.12659/MSM.911849.
Gao S, Zhou J, Liu N, Wang L, Gao Q, Wu Y, et al. Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13. J Mol Cell Cardiol. 2015;85:131–9. https://doi.org/10.1016/j.yjmcc.2015.04.025.
Li L, Gan H, Jin H, Fang Y, Yang Y, Zhang J, et al. Astragaloside iv promotes microglia/macrophages M2 polarization and enhances neurogenesis and angiogenesis through pparγ pathway after cerebral ischemia/reperfusion injury in rats. Int Immunopharmacol. 2021;92: 107335. https://doi.org/10.1016/j.intimp.2020.107335.
Wu MM, Wang QM, Huang BY, Mai CT, Wang CL, Wang TT, et al. Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization. Pharmacol Res. 2021;172: 105796. https://doi.org/10.1016/j.phrs.2021.105796.
Long J, Liu XK, Kang ZP, Wang MX, Zhao HM, Huang JQ, et al. Ginsenoside RG1 ameliorated experimental colitis by regulating the balance of M1/M2 macrophage polarization and the homeostasis of intestinal flora. Eur J Pharmacol. 2022;917: 174742. https://doi.org/10.1016/j.ejphar.2022.174742.
Zhu Y, Li X, Chen J, Chen T, Shi Z, Lei M, et al. The pentacyclic triterpene lupeol switches M1 macrophages to M2 and ameliorates experimental inflammatory bowel disease. Int Immunopharmacol. 2016;30:74–84. https://doi.org/10.1016/j.intimp.2015.11.031.
Guo R, Meng Q, Wang B, Li F. Anti-inflammatory effects of platycodin D on dextran sulfate sodium (DSS) induced colitis and E. Coli lipopolysaccharide (LPS) induced inflammation. Int Immunopharmacol. 2021;94: 107474. https://doi.org/10.1016/j.intimp.2021.107474.
Qi J, Xue Q, Kuang L, Xie L, Luo R, Nie X. Berberine alleviates cisplatin-induced acute kidney injury by regulating mitophagy via pink 1/parkin pathway. Transl Androl Urol. 2020;9:1712–24. https://doi.org/10.21037/tau-20-1129.
Wang S, Zheng Y, Jin S, Fu Y, Liu Y. Dioscin protects against cisplatin-induced acute kidney injury by reducing ferroptosis and apoptosis through activating NRF2/HO-1 signaling. Antioxidants. 2022;11:2443. https://doi.org/10.3390/antiox11122443.
Acknowledgements
Not applicable.
Funding
This study was supported by the National Natural Science Foundation of China (Grant Numbers 82074171, 82374238, 82003611).
Author information
Authors and Affiliations
Contributions
DLZ conceptualized, and drafted the manuscript. HHJ, XZY and SXZ performed the literature searches and drafted the manuscript. XDX and SL collated and verified all the references and proofread the diagrams in the manuscript. XDX, SL and YL were involved in the conceptualization of the manuscript, writing, review, and editing. All authors have agreed to be accountable for all aspects of this study, ensuring its integrity and accuracy.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All the authors declared no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Zhang, D., Jiang, H., Yang, X. et al. Traditional Chinese Medicine and renal regeneration: experimental evidence and future perspectives. Chin Med 19, 77 (2024). https://doi.org/10.1186/s13020-024-00935-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s13020-024-00935-9