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Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria

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Abstract

Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in acute kidney injury (AKI), which is a risk factor for the development of chronic kidney disease (CKD). Apelin is a bioactive peptide that protects against AKI by alleviating inflammation, inhibiting apoptosis, and preventing lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of apelin on mitochondria in cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in cisplatin-induced AKI mice. In vitro, apelin inhibited the cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting protein optic atrophy 1 (OPA1) downregulation. Apelin co-treatment reversed the decreased levels of the deacetylase, Sirt3, and the increased levels of protein acetylation in mitochondria of cisplatin-stimulated cells. Overall, apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model, apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of Sirt3 and OPA1 expression in apelin-treated AKI mice was also observed. Finally, exogenous administration of apelin normalized the serum level of creatinine and urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and Sirt3. In conclusion, we demonstrated that apelin ameliorates renal functions by protecting tubular mitochondria through Sirt3 upregulation, which is a novel protective mechanism of apelin in AKI. These results suggest that apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.

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References

  • Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA 105:14447–14452

    Article  PubMed  PubMed Central  Google Scholar 

  • Bhargava P, Schnellmann RG (2017) Mitochondrial energetics in the kidney. Nat Rev Nephrol 13:629–646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bircan B, Çakır M, Kırbağ S, Gül HF (2016) Effect of apelin hormone on renal ischemia/reperfusion induced oxidative damage in rats. Ren Fail 38(7):1122–1128

    Article  PubMed  CAS  Google Scholar 

  • Bonventre JV, Yang L (2011) Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121:4210–4221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boulkeroua C, Ayari H, Khalfaoui T, Lafrance M, Besserer-Offroy É, Ekindi N, Sabbagh R, Dumaine R, Lesur O, Sarret P, Chraibi A (2019) Apelin-13 regulates vasopressin-induced aquaporin-2 expression and trafficking in kidney collecting duct cells. Cell Physiol Biochem 53:687–700

    Article  PubMed  CAS  Google Scholar 

  • Chawla LS, Eggers PW, Star RA, Kimmel PL (2014) Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371:58–66

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Wan D, Wang L, Peng A, Xiao H, Petersen RB, Liu C, Zheng L, Huang K (2015) Apelin protects against acute renal injury by inhibiting TGF-β1. Biochim Biophys Acta 1852:1278–1287

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Wang L, Wang W, Cheng C, Zhang Y, Zhou Y, Wang C, Miao X, Wang J, Wang C, Li J, Zheng L, Huang K (2017) ELABELA and an ELABELA fragment protect against AKI. J Am Soc Nephrol 28:2694–2707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cooper DM (2003) Regulation and organization of adenylyl cyclases and cAMP. Biochem J 375(Pt 3):517–529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gholampour F, Bagheri A, Barati A, Masoudi R, Owji SM (2020) Remote ischemic perconditioning modulates apelin expression after renal ischemia-reperfusion injury. J Surg Res 247:429–437

    Article  PubMed  CAS  Google Scholar 

  • Giralt A, Hondares E, Villena JA, Ribas F, Díaz-Delfín J, Giralt M, Iglesias R, Villarroya F (2011) Peroxisome proliferator-activated receptor-gamma coactivator-1alpha controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype. J Biol Chem 286:16958–16966

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grancara S, Zonta F, Ohkubo S, Brunati AM, Agostinelli E, Toninello A (2015) Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation. Amino Acids 47:869–883

    Article  PubMed  CAS  Google Scholar 

  • Gurevich VV, Gurevich EV (2006) The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol Ther 110(3):465–502

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Handschin C, Spiegelman BM (2006) Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27:728–735

    Article  PubMed  CAS  Google Scholar 

  • Ishimoto Y, Inagi R (2016) Mitochondria: a therapeutic target in acute kidney injury. Nephrol Dial Transplant 31:1062–1069

    Article  PubMed  CAS  Google Scholar 

  • Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS ONE 5:e1170701–e1170713

    Article  Google Scholar 

  • Li Y, Ye Z, Lai W, Rao J, Huang W, Zhang X, Yao Z, Lou T (2017) Activation of sirtuin 3 by silybin attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Front Pharmacol 8:17801–17812

    Google Scholar 

  • Liesa M, Palacín M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89:799–845

    Article  PubMed  CAS  Google Scholar 

  • Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV Jr, Weissman S, Verdin E, Schwer B (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27:8807–8814

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lu Y, Zhu X, Liang GX, Cui RR, Liu Y, Wu SS, Liang QH, Liu GY, Jiang Y, Liao XB, Xie H, Zhou HD, Wu XP, Yuan LQ, Liao EY (2012) Apelin-APJ induces ICAM-1, VCAM-1 and MCP-1 expression via NF-κB/JNK signal pathway in human umbilical vein endothelial cells. Amino Acids 43:2125–2136

    Article  PubMed  CAS  Google Scholar 

  • McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–R560

    Article  PubMed  CAS  Google Scholar 

  • Morigi M, Perico L, Rota C, Longaretti L, Conti S, Rottoli D, Novelli R, Remuzzi G, Benigni A (2015) Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J Clin Invest 125:715–726

    Article  PubMed  PubMed Central  Google Scholar 

  • Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007

    Article  PubMed  CAS  Google Scholar 

  • Perico L, Morigi M, Benigni A (2016) Mitochondrial sirtuin 3 and renal diseases. Nephron 134:14–19

    Article  PubMed  CAS  Google Scholar 

  • Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J, Zhang R, He M, Lu Y, Liu C, Duan W, Yu Z, Zhou Z (2015) SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 11:1037–1051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, Arbiser JL, Walker DI, Jones DP, Gius D, Gupta MP (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 6:665601–665616

    Article  Google Scholar 

  • Pisarenko O, Shulzhenko V, Studneva I, Pelogeykina Y, Timoshin A, Anesia R, Valet P, Parini A, Kunduzova O (2015) Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury. Br J Pharmacol 172:2933–2945

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pouresmaeili-Babaki E, Esmaeili-Mahani S, Abbasnejad M, Ravan H (2018) Protective effect of neuropeptide apelin-13 on 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y dopaminergic cells: involvement of its antioxidant and antiapoptotic properties. Rejuvenation Res 21:162–167

    Article  PubMed  CAS  Google Scholar 

  • Soltoff SP (1986) ATP and the regulation of renal cell function. Annu Rev Physiol 48:9–31

    Article  PubMed  CAS  Google Scholar 

  • Szeto HH (2017) Pharmacologic approaches to improve mitochondrial function in AKI and CKD. J Am Soc Nephrol 28:2856–2865

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tang M, Huang Z, Luo X, Liu M, Wang L, Qi Z, Huang S, Zhong J, Chen JX, Li L, Wu D, Chen L (2019) Ferritinophagy activation and sideroflexin1-dependent mitochondria iron overload is involved in apelin-13-induced cardiomyocytes hypertrophy. Free Radic Biol Med 134:445–457

    Article  PubMed  CAS  Google Scholar 

  • Thadhani R, Pascual M, Bonventre JV (1996) Acute renal failure. N Engl J Med 334:1448–1460

    Article  PubMed  CAS  Google Scholar 

  • Torrens-Mas M, Oliver J, Roca P, Sastre-Serra J (2017) SIRT3: oncogene and tumor suppressor in cancer. Cancers (basel) 9:1–10

    Article  CAS  Google Scholar 

  • Tresguerres M, Levin LR, Buck J (2011) Intracellular cAMP signaling by soluble adenylyl cyclase. Kidney Int 79(12):1277–1288

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM (2006) Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 3:333–341

    Article  PubMed  CAS  Google Scholar 

  • Verdin E, Hirschey MD, Finley LW, Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35:669–675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang LY, Diao ZL, Zhang DL, Zheng JF, Zhang QD, Ding JX, Liu WH (2014) The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis. Amino Acids 46:2693–2704

    Article  PubMed  CAS  Google Scholar 

  • Wang LY, Diao ZL, Zheng JF, Wu YR, Zhang QD, Liu WH (2017) Apelin attenuates TGF-β1-induced epithelial to mesenchymal transition via activation of PKC-ε in human renal tubular epithelial cells. Peptides 96:44–52

    Article  PubMed  CAS  Google Scholar 

  • Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, Lucia S, Adorini L, D’Agati VD, Levi J, Rosenberg A, Kopp JB, Gius DR, Saleem MA, Levi M (2016) G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. J Am Soc Nephrol 27:1362–1378

    Article  PubMed  CAS  Google Scholar 

  • Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884

    Article  PubMed  CAS  Google Scholar 

  • Wu YT, Lee HC, Liao CC, Wei YH (2013) Regulation of mitochondrial F(o)F(1)ATPase activity by Sirt3-catalyzed deacetylation and its deficiency in human cells harboring 4977bp deletion of mitochondrial DNA. Biochim Biophys Acta 1832:216–227

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Liu H, Liu F, Dong Z (2014) Mitochondrial dysregulation and protection in cisplatin nephrotoxicity. Arch Toxicol 88:1249–1256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhan M, Brooks C, Liu F, Sun L, Dong Z (2013) Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int 83:568–581

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang L, Li F, Su X, Li Y, Wang Y, Fang R, Guo Y, Jin T, Shan H, Zhao X, Yang R, Shan H, Liang H (2019) Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction. Exp Mol Med 51:7301–7312

    Article  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant No. 82003833), Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (Grant No. ZYLX201824), and the Research Foundation (Nature) of Capital Medical University (Grant No. PYZ2018051). We thank Michal Bell, PhD, and Mitchell Arico from Liwen Bianji (Edanz) (https://www.liwenbianji.cn) for editing the language of a draft of this manuscript.

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  1. Department of Nephrology, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, 100050, China

    Yi-Ming Guan, Zong-Li Diao, Hong-Dong Huang, Qi-Dong Zhang, Li-Yan Wang & Wen-Hu Liu

  2. Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China

    Jun-Fang Zheng

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  1. Yi-Ming Guan
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Guan, YM., Diao, ZL., Huang, HD. et al. Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria. Amino Acids 53, 1229–1240 (2021). https://doi.org/10.1007/s00726-021-03028-1

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