Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells

Kidney Int. 2006 Oct;70(8):1447-55. doi: 10.1038/sj.ki.5001704. Epub 2006 Sep 6.

Abstract

Chronic proteinuria appears to be a key factor in tubulointerstitial damage. Recent studies have emphasized a pathogenic role of endoplasmic reticulum (ER) stress which is induced by the accumulation of misfolded proteins in ER, extracellular stress, etc. In the present study, we investigated ER stress and ER stress-induced apoptosis in proximal tubular cells (PTCs). Immortalized rat PTCs (IRPTCs) were cultured with bovine serum albumin (BSA). The viability of IRPTCs decreased proportionately with BSA overload in a time-dependent manner. Quantitative real-time polymerase chain reaction analysis revealed that 40 mg/ml BSA increases mRNA of ER stress markers by 7.7- and 4.6-fold (glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150), respectively) as compared to control. The increased expression of ORP150 and GRP78 in IRPTCs with albumin overload was detected by Western blot and immunofluorescence study. These in vitro observations were supported by in vivo studies, which demonstrated that ER stress proteins were upregulated at PTCs in experimental proteinuric rats. Furthermore, increased ER stress-induced apoptosis and activation of caspase-12 were observed in IRPTCs with albumin overload and kidneys of experimental proteinuric rats. We confirmed that apoptotic cell death was attenuated by co-incubation with caspase-3 inhibitor or calpain inhibitors. These results indicate that the ER stress-induced apoptosis pathway contributed to the insult of tubular cells by proteinuria. In conclusion, renal tubular cells exposed to high protein load suffer from ER stress. ER stress may subsequently lead to tubular damage by activation of caspase-12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylates / pharmacology
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Calpain / antagonists & inhibitors
  • Calpain / genetics
  • Calpain / metabolism
  • Caspase 12
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / pathology
  • Kidney Tubules, Proximal / physiopathology
  • Leupeptins / pharmacology
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Oligopeptides / pharmacology
  • Proteins / genetics
  • Proteins / metabolism
  • Proteinuria / physiopathology*
  • Rats
  • Serum Albumin, Bovine / pharmacology*
  • Stress, Physiological

Substances

  • Acrylates
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Hspa5 protein, rat
  • Leupeptins
  • Molecular Chaperones
  • Oligopeptides
  • PD 150606
  • Proteins
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • oxygen-regulated proteins
  • acetylleucyl-leucyl-norleucinal
  • Serum Albumin, Bovine
  • Calpain
  • Casp12 protein, rat
  • Casp3 protein, rat
  • Caspase 12
  • Caspase 3
  • Caspases