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Impact of high salt diets on CHOP-mediated apoptosis and renal fibrosis in a rat model

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Abstract

Background

Prolonged and excessive salt intake accelerates oxidative stress in kidney tissues, which brings about ER stress. The PERK/ATF4/CHOP/BCL-2 signaling pathway has an essential role in ER stress-induced apoptosis. The present study aimed to investigate the effect of high salt diets on the development of renal fibrosis through CHOP-mediated apoptosis.

Methods and results

Twenty-five male Wistar rats were randomly divided into five groups (n = 5 each). Groups 1–5 were treated with 0%, 0.5%, 1%, 1.2%, 1.5% of NaCl dissolved in distilled water, respectively, for 8 weeks. To detect the degree of renal tubular damage, urinary KIM-1 was measured. The slides of renal tissues were stained via Masson’s Trichrome staining methods for fibrosis detection. The relative gene expression of ATF4, CHOP, and BCl-2 in renal tissues were analyzed using the qRT-PCR method. The results revealed no significant difference between the urea, creatinine, and urine flow rate of the rats receiving different concentrations of NaCl (groups 2–5) and those of the control group (group 1). The rats treated with 1.5% NaCl (group 5) showed significant elevations in urinary KIM-1 and the mRNA level of CHOP compared to the control group. Mild renal fibrosis was also observed in group 5.

Conclusions

Excessive salt intake leads to fibrosis as it induces the PERK/ATF4/CHOP/BCL-2 signaling pathway in renal tissues. KIM-1 is detectable in urine before the impairment of renal function which can be used as a diagnostic marker to prevent the development of progressive renal failure.

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Abbreviations

ATF4:

Activating transcription factor 4

Bcl-2:

B cell lymphoma-2

CHOP:

C/EBP homologous protein

CT:

Cycle threshold

DSS:

Dahl salt-sensitive

ECM:

Extracellular matrix

eIF2α:

Eukaryotic translation initiation factor 2α

ER:

Endoplasmic reticulum

FRAP:

Ferric reducing antioxidant power

GFR:

Glomerular filtration rate

GPx:

Glutathione peroxidase

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

H and E:

Hematoxylin and eosin

HIF-1α:

Hypoxia induced factor 1α

KIM-1:

Kidney injury molecule 1

MDA:

Malondialdehyde

M-T:

Masson’s trichrome

NOX:

NADPH oxidase

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

RF:

Renal failure

ROS:

Reactive oxygen species

SHR:

Spontaneously hypertensive rats

SOD:

Superoxide dismutase

TBA:

Thiobarbituric acid

UCP-2:

Uncoupling protein 2

References

  1. Nogueira A, Pires MJ, Oliveira PA (2017) Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In Vivo (Athens, Greece) 31(1):1–22

    CAS  Google Scholar 

  2. Hewitson TD (2009) Renal tubulointerstitial fibrosis: common but never simple. Am J Physiol Renal Physiol 296(6):F1239–F1244

    Article  CAS  Google Scholar 

  3. Hayakawa Y, Komaki H, Minatoguchi S, Yamada Y, Kanamori H, Nishigaki K et al (2020) High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (pro)renin receptors and AT1 receptors in spontaneously hypertensive rats. Clin Exp Nephrol 24(7):582–589

    Article  CAS  Google Scholar 

  4. Vara-Messler M, Mukdsi JH, Osieki NI, Benizio E, Repossi GM, Ajayi EIO et al (2020) Eicosapentaenoic acid prevents salt sensitivity in diabetic rats and decreases oxidative stress. Nutrition 72:110644

    Article  CAS  Google Scholar 

  5. Sies H (2015) Oxidative stress: a concept in redox biology and medicine. Redox Biol 4:180–183

    Article  CAS  Google Scholar 

  6. Tian N, Moore RS, Phillips WE, Lin L, Braddy S, Pryor JS et al (2008) NADPH oxidase contributes to renal damage and dysfunction in Dahl salt-sensitive hypertension. Am J Physiol Regul Integr Comp Physiol 295(6):R1858–R1865

    Article  CAS  Google Scholar 

  7. Babior BM (2004) NADPH oxidase. Curr Opin Immunol 16(1):42–47

    Article  CAS  Google Scholar 

  8. Della Penna SL, Cao G, Carranza A, Zotta E, Gorzalczany S, Cerrudo CS et al (2014) Renal overexpression of atrial natriuretic peptide and hypoxia inducible factor-1α as adaptive response to a high salt diet. BioMed Res Int 2014:936978

    PubMed  PubMed Central  Google Scholar 

  9. Su LJ, Zhang JH, Gomez H, Murugan R, Hong X, Xu D et al (2019) Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev 2019:5080843

    PubMed  PubMed Central  Google Scholar 

  10. Lee WS, Yoo WH, Chae HJ (2015) ER stress and autophagy. Curr Mol Med 15(8):735–745

    Article  CAS  Google Scholar 

  11. Hu H, Tian M, Ding C, Yu S (2018) The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol 9:3083

    Article  CAS  Google Scholar 

  12. Yum V, Carlisle RE, Lu C, Brimble E, Chahal J, Upagupta C et al (2017) Endoplasmic reticulum stress inhibition limits the progression of chronic kidney disease in the Dahl salt-sensitive rat. Am J Physiol Renal Physiol 312(1):F230–F244

    Article  CAS  Google Scholar 

  13. Korennykh A, Walter P (2012) Structural basis of the unfolded protein response. Annu Rev Cell Dev Biol 28:251–277

    Article  CAS  Google Scholar 

  14. Liu Z, Shi Q, Song X, Wang Y, Wang Y, Song E et al (2016) Activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) cascade shows an essential role in the ER stress-induced sensitization of tetrachlorobenzoquinone-challenged PC12 Cells to ROS-mediated apoptosis via death receptor 5 (DR5) signaling. Chem Res Toxicol 29(9):1510–1518

    Article  CAS  Google Scholar 

  15. Chen Y, Gui D, Chen J, He D, Luo Y, Wang N (2014) Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats. Cell Physiol Biochem 33(6):1975–1987

    Article  CAS  Google Scholar 

  16. Cao J, Dai DL, Yao L, Yu HH, Ning B, Zhang Q et al (2012) Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem 364(1–2):115–129

    Article  CAS  Google Scholar 

  17. Tsukano H, Gotoh T, Endo M, Miyata K, Tazume H, Kadomatsu T et al (2010) The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques. Arterioscler Thromb Vasc Biol 30(10):1925–1932

    Article  CAS  Google Scholar 

  18. Iurlaro R, Muñoz-Pinedo C (2016) Cell death induced by endoplasmic reticulum stress. FEBS J 283(14):2640–2652

    Article  CAS  Google Scholar 

  19. Siddiqui WA, Ahad A, Ahsan H (2015) The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol 89(3):289–317

    Article  CAS  Google Scholar 

  20. Brenner C, Grimm S (2006) The permeability transition pore complex in cancer cell death. Oncogene 25(34):4744–4756

    Article  CAS  Google Scholar 

  21. Wei SY, Wang YX, Zhang QF, Zhao SL, Diao TT, Li JS et al (2017) Multiple mechanisms are involved in salt-sensitive hypertension-induced renal injury and interstitial fibrosis. Sci Rep 7:45952

    Article  CAS  Google Scholar 

  22. van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA (2007) Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol 212(2):209–217

    Article  Google Scholar 

  23. Moresco RN, Bochi GV, Stein CS, De Carvalho JAM, Cembranel BM, Bollick YS (2018) Urinary kidney injury molecule-1 in renal disease. Clin Chim Acta Int J Clin Chem 487:15–21

    Article  CAS  Google Scholar 

  24. Karimi N, Ghadimi D, Fathi M (2020) The inhibitory effect of biochanin a on hepatic cholesterol biosynthesis in high glucose-induced steatosis in HepG2 cells. RABMS 6(3)

  25. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11(4):381–389

    Article  CAS  Google Scholar 

  26. Mohammed-Ali Z, Lu C, Marway MK, Carlisle RE, Ask K, Lukic D et al (2017) Endoplasmic reticulum stress inhibition attenuates hypertensive chronic kidney disease through reduction in proteinuria. Sci Rep 7:41572

    Article  CAS  Google Scholar 

  27. Bruch J, Xu H, Rosler TW, De Andrade A, Kuhn PH, Lichtenthaler SF et al (2017) PERK activation mitigates tau pathology in vitro and in vivo. EMBO Mol Med 9(3):371–384

    Article  CAS  Google Scholar 

  28. Sabbisetti VS, Waikar SS, Antoine DJ, Smiles A, Wang C, Ravisankar A et al (2014) Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol 25(10):2177–2186

    Article  CAS  Google Scholar 

  29. Nogare AL, Veronese FV, Carpio VN, Montenegro RM, Pedroso JA, Pegas KL et al (2015) Kidney injury molecule-1 expression in human kidney transplants with interstitial fibrosis and tubular atrophy. BMC Nephrol 16:19

    Article  Google Scholar 

  30. Yu HC, Burrell LM, Black MJ, Wu LL, Dilley RJ, Cooper ME et al (1998) Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation 98(23):2621–2628

    Article  CAS  Google Scholar 

  31. Matavelli LC, Zhou X, Varagic J, Susic D, Frohlich ED (2007) Salt loading produces severe renal hemodynamic dysfunction independent of arterial pressure in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 292(2):H814–H819

    Article  CAS  Google Scholar 

  32. Susic D, Frohlich ED, Kobori H, Shao W, Seth D, Navar LG (2011) Salt-induced renal injury in SHRs is mediated by AT1 receptor activation. J Hypertens 29(4):716–723

    Article  CAS  Google Scholar 

  33. Greenwood M, Greenwood MP, Paton JF, Murphy D (2015) Transcription factor CREB3L1 regulates endoplasmic reticulum stress response genes in the osmotically challenged rat hypothalamus. PloS One 10(4):e0124956

    Article  Google Scholar 

  34. Cao W, Li A, Wang L, Zhou Z, Su Z, Bin W et al (2015) A salt-induced reno-cerebral reflex activates renin-angiotensin systems and promotes CKD progression. J Am Soc Nephrol 26(7):1619–1633

    Article  CAS  Google Scholar 

  35. Tanada Y, Okuda J, Kato T, Minamino-Muta E, Murata I, Soga T et al (2017) The metabolic profile of a rat model of chronic kidney disease. PeerJ 5:e3352

    Article  Google Scholar 

  36. Hijmans RS, Shrestha P, Sarpong KA, Yazdani S, El Masri R, de Jong WHA et al (2017) High sodium diet converts renal proteoglycans into pro-inflammatory mediators in rats. PloS One 12(6):e0178940

    Article  Google Scholar 

  37. Washino S, Hosohata K, Jin D, Takai S, Miyagawa T (2018) Early urinary biomarkers of renal tubular damage by a high-salt intake independent of blood pressure in normotensive rats. Clin Exp Pharmacol Physiol 45(3):261–268

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to show their gratitude to Biochemistry Department and Zanjan University of Medical Sciences for their support; and to thank the reviewers for their so-called insights.

Funding

This work was supported by Zanjan University of Medical Sciences and is a part of Khadive´s MSc thesis which was approved by thesis code A-12-1260-3 in Deputy of Research and Technology of Zanjan University of Medical Sciences.

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Authors and Affiliations

  1. Biochemistry Department, School of Medicine, Zanjan University of Medical Sciences, Mahdavi Street, Zanjan, Iran

    Tooka Khadive, Darya Ghadimi & Mina Hemmati

  2. Tissue Engineering Department, Nanobiotechnology Research Center, Avicenna Research Institute, Tehran, Iran

    Hannaneh Golshahi

Authors
  1. Tooka Khadive
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  2. Darya Ghadimi
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  3. Mina Hemmati
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  4. Hannaneh Golshahi
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Contributions

DG and TK contributed to the conception or design of the work. DG, TK and HG contributed to acquisition, analysis, or interpretation of data. DG and MH contributed to drafting the work or revising it critically for important intellectual content. The manuscript has been read and approved by all the authors and each author believes that the manuscript represents honest work.

Corresponding author

Correspondence to Darya Ghadimi.

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Conflict of interest

All contributing authors declare no conflicts of interest.

Data availability

The data supporting findings of this study are available on request from the corresponding author. The data are not publicy available due to privacy or ethical restrictions.

Ethical approval

Protocols for experiment on animals were approved by ethics code IR.ZUMS.REC.1399.019 in the Ethics committee of Zanjan University of Medical Sciences.

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Khadive, T., Ghadimi, D., Hemmati, M. et al. Impact of high salt diets on CHOP-mediated apoptosis and renal fibrosis in a rat model. Mol Biol Rep 48, 6423–6433 (2021). https://doi.org/10.1007/s11033-021-06644-y

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