Molecular Medicine

, Volume 17, Issue 11–12, pp 1295–1305 | Cite as

Endoplasmic Reticulum Stress Implicated in the Development of Renal Fibrosis

  • Chih-Kang Chiang
  • Shih-Ping Hsu
  • Cheng-Tien Wu
  • Jenq-Wen Huang
  • Hui-Teng Cheng
  • Yi-Wen Chang
  • Kuan-Yu Hung
  • Kuan-Dun Wu
  • Shing-Hwa Liu
Research Article


Endoplasmic reticulum (ER) stress-associated apoptosis plays a role in organ remodeling after insult. The effect of ER stress on renal tubular damage and fibrosis remains controversial. This study aims to investigate whether ER stress is involved in tubular destruction and interstitial fibrosis in vivo. Renal cell apoptosis was proven by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) stain and poly-ADP ribose polymerase expression in the unilateral ureteral obstruction (UUO) kidney. ER stress was evoked and confirmed by the upregulation of glucose-regulated protein 78 (GRP78) and the common Lys-Asp-Glu-Leu (KDEL) motif of ER retention proteins after UUO. ER stress-associated proapoptotic signals, including B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2-associated × protein (BAX) expression, caspase-12 and c-Jun N-terminal kinase (JNK) phosphorylation, were activated in the UUO kidney. Prolonged ER stress attenuated both unsplicing and splicing X-box binding protein 1 (XBP-1) protein expression, but continued to activate inositol-requiring 1α (IRE1α)-JNK phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α subunit (eIF2α), activating transcription factor (ATF)-4, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleavage activating transcription factor 6 (cATF6)-CHOP signals, which induce ER stress-related apoptosis but attenuate adaptive unfolded protein responses in UUO kidneys. However, renal apoptosis and fibrosis were attenuated in candesartan-treated UUO kidney. Candesartan was associated with maintenance of XBP-1 expression and attenuated ATF4, cATF6 and CHOP protein expression. Taken together, results show that overwhelming ER stress leads to renal cell apoptosis and subsequent fibrosis; and candesartan, at least in part, restores renal integrity by blocking ER stress-related apoptosis. Reducing ER stress may present a way to attenuate renal fibrosis.



We thank the Second Core Laboratory of the Department of Medical Research in the National Taiwan University Hospital for equipment and facility support. This work was supported by grants from the National Science Council (to C-K Chiang: NSC-97-2314-B-002-051 and NSC-100-2314-B-002-069) and the Taiwan University Hospital (to C-K Chiang: NTUH-99-S-1333 and 98-FTN01).

Supplementary material

10020_2011_17111295_MOESM1_ESM.pdf (164 kb)
Supplementary material, approximately 164 KB.


  1. 1.
    Hewitson TD. (2009) Renal tubulointerstitial fibrosis: common but never simple. Am. J. Physiol. Renal Physiol. 296:F1239–44.CrossRefGoogle Scholar
  2. 2.
    Risdon RA, Sloper JC, De Wardener HE. (1968) Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet. 2:363–6.CrossRefGoogle Scholar
  3. 3.
    Liu Y. (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 69:213–7.CrossRefGoogle Scholar
  4. 4.
    Mimura I, Nangaku M. (2010) The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat. Rev. Nephrol. 6:667–78.CrossRefGoogle Scholar
  5. 5.
    Nangaku M. (2006) Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J. Am. Soc. Nephrol. 17:17–25.CrossRefGoogle Scholar
  6. 6.
    Docherty NG, O’Sullivan OE, Healy DA, Fitzpatrick JM, Watson RW. (2006) Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction. Am. J. Physiol. Renal Physiol. 290:F4–13.CrossRefGoogle Scholar
  7. 7.
    Klahr S, Morrissey J. (2002) Obstructive nephropathy and renal fibrosis. Am. J. Physiol. Renal Physiol. 283:F861–75.CrossRefGoogle Scholar
  8. 8.
    Inagi R. (2010) Endoplasmic reticulum stress as a progression factor for kidney injury. Curr. Opin. Pharmacol. 10:156–65.CrossRefGoogle Scholar
  9. 9.
    Malhotra JD, Kaufman RJ. (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9:2277–93.CrossRefGoogle Scholar
  10. 10.
    Yoshida H. (2007) ER stress and diseases. FEBS J 274:630–58.CrossRefGoogle Scholar
  11. 11.
    Inagi R, et al. (2005) Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation. Kidney Int. 68:2639–50.CrossRefGoogle Scholar
  12. 12.
    Hotamisligil GS. (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 140:900–17.CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Hong M, Li M, Mao C, Lee AS. (2004) Endoplasmic reticulum stress triggers an acute proteasome-dependent degradation of ATF6. J. Cell. Biochem. 92:723–32.CrossRefGoogle Scholar
  14. 14.
    Shen J, Prywes R. (2004) Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6. J. Biol. Chem. 279:43046–51.CrossRefGoogle Scholar
  15. 15.
    Oyadomari S, Araki E, Mori M. (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis. 7:335–45.CrossRefGoogle Scholar
  16. 16.
    Han D, et al. (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 138:562–75.CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Korennykh AV, et al. (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature. 457:687–93.CrossRefGoogle Scholar
  18. 18.
    Cybulsky AV. (2010) Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int. 77:187–93.CrossRefGoogle Scholar
  19. 19.
    Okada K, et al. (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation. 110:705–12.CrossRefGoogle Scholar
  20. 20.
    Mu YP, Ogawa T, Kawada N. (2010) Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methioninecholine-deficient diet. Lab. Invest. 90:245–56.CrossRefGoogle Scholar
  21. 21.
    Tamaki N, et al. (2008) CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am. J. Physiol. Gastrointest. Liver Physiol. 294:G498–505.CrossRefGoogle Scholar
  22. 22.
    Dickhout JG, Carlisle RE, Austin RC. (2011) Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease endoplasmic reticulum stress as a mediator of pathogenesis. Circ. Res. 108:629–42.CrossRefGoogle Scholar
  23. 23.
    Dihazi H, et al. (2011) Proteomics characterization of cell model with renal fibrosis phenotype: osmotic stress as fibrosis triggering factor. J. Proteomics. 74:304–18.CrossRefGoogle Scholar
  24. 24.
    Higgins DF, et al. (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117:3810–20.PubMedPubMedCentralGoogle Scholar
  25. 25.
    el-Dahr SS, et al. (1993) Upregulation of reninangiotensin system and downregulation of kallikrein in obstructive nephropathy. Am. J. Physiol. 264:F874–81.PubMedGoogle Scholar
  26. 26.
    Badiola N, et al. (2011) Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12. Cell Death Dis. 2:e149.CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Lee JY, et al. (2011) Albumin-induced epithelialmesenchymal transition and ER stress are regulated through a common ROS-c-Src kinasemTOR pathway: effect of imatinib mesylate. Am. J. Physiol. Renal Physiol. 300:F1214–22.CrossRefGoogle Scholar
  28. 28.
    Yeh CH, Chiang HS, Lai TY, Chien CT. (2011) Unilateral ureteral obstruction evokes renal tubular apoptosis via the enhanced oxidative stress and endoplasmic reticulum stress in the rat. Neurourol. Urodyn. 30:472–9.CrossRefGoogle Scholar
  29. 29.
    Moriyama T, et al.(1997) TCV-116 inhibits interstitial fibrosis and HSP47 mRNA in rat obstructive nephropathy. Kidney Int. Suppl. 63:S232–5.PubMedGoogle Scholar
  30. 30.
    Yu C, Gong R, Rifai A, Tolbert EM, Dworkin LD. (2007) Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection. J. Am. Soc. Nephrol. 18:750–9.CrossRefGoogle Scholar
  31. 31.
    Remuzzi G, et al. (1999) Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals. J. Am. Soc. Nephrol. 10:1542–9.PubMedGoogle Scholar
  32. 32.
    Munro S, Pelham HR. (1987) A C-terminal signal prevents secretion of luminal ER proteins. Cell. 48:899–907.CrossRefGoogle Scholar
  33. 33.
    Ron D, Walter P. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell. Biol. 8:519–29.CrossRefGoogle Scholar
  34. 34.
    Lin JH, et al. (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science. 318:944–9.CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Lisbona F, et al. (2009) BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol. Cell. 33:679–91.CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Muruganandan S, Cribb AE. (2006) Calpain-induced endoplasmic reticulum stress and cell death following cytotoxic damage to renal cells. Toxicol. Sci. 94:118–28.CrossRefGoogle Scholar
  37. 37.
    Ryan PM, Bedard K, Breining T, Cribb AE. (2005) Disruption of the endoplasmic reticulum by cytotoxins in LLC-PK1 cells. Toxicol. Lett. 159:154–63.CrossRefGoogle Scholar
  38. 38.
    Pallet N, et al. (2008) Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death. Am. J. Transplant. 8:2283–96.CrossRefGoogle Scholar
  39. 39.
    Kawakami T, Inagi R, Wada T, Tanaka T, Fujita T, Nangaku M. (2010) Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. Am. J. Physiol. Renal Physiol. 299:F568–76.CrossRefGoogle Scholar
  40. 40.
    Sun HL, et al. (2009) ACE-inhibitor suppresses the apoptosis induced by endoplasmic reticulum stress in renal tubular in experimental diabetic rats. Exp. Clin. Endocrinol. Diabetes. 117:336–44.CrossRefGoogle Scholar
  41. 41.
    Qi W, et al. (2011) Attenuation of diabetic nephropathy in diabetes rats induced by streptozotocin by regulating the endoplasmic reticulum stress inflammatory response. Metabolism. 60:594–603.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Chih-Kang Chiang
    • 1
    • 2
  • Shih-Ping Hsu
    • 2
    • 3
  • Cheng-Tien Wu
    • 4
  • Jenq-Wen Huang
    • 2
  • Hui-Teng Cheng
    • 2
  • Yi-Wen Chang
    • 1
    • 2
  • Kuan-Yu Hung
    • 2
  • Kuan-Dun Wu
    • 2
  • Shing-Hwa Liu
    • 4
  1. 1.Department of Integrated Diagnostics and TherapeuticsNational Taiwan University Hospital and National Taiwan University College of MedicineTaipeiTaiwan
  2. 2.Department of Internal MedicineNational Taiwan University Hospital and National Taiwan University College of MedicineTaipeiTaiwan
  3. 3.Division of NephrologyFar Eastern Memorial HospitalTaipeiTaiwan
  4. 4.Institute of Toxicology, School of MedicineNational Taiwan UniversityTaipeiTaiwan

Personalised recommendations