Renal protection by low dose irbesartan in diabetic nephropathy is paralleled by a reduction of inflammation, not of endoplasmic reticulum stress

Biochim Biophys Acta. 2014 Apr;1842(4):558-65. doi: 10.1016/j.bbadis.2014.01.001. Epub 2014 Jan 10.

Abstract

Diabetes can disrupt endoplasmic reticulum (ER) homeostasis which leads to ER stress. ER stress-induced renal apoptosis seems to be involved in the development of diabetic nephropathy. The present study was designed to investigate the contribution of reduced ER stress to the beneficial effects of an angiotensin receptor blocker. Insulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats. After 2weeks animals were treated with 0.7mg/kg/day irbesartan. Blood glucose, blood pressure and protein excretion were assessed. Expression of ER stress markers was measured by real-time PCR. Immunohistochemistry was performed to detect markers of ER stress, renal damage and infiltrating cells. Glomerulosclerosis and apoptosis were evaluated. Diabetic mRen2-transgenic rats developed renal injury with proteinuria, tubulointerstitial cell proliferation as well as glomerulosclerosis and podocyte injury. Moreover, an increase in inflammation, podocyte ER stress and apoptosis was detected. Irbesartan somewhat lowered blood pressure and reduced proteinuria, tubulointerstitial cell proliferation and glomerulosclerosis. Podocyte damage was ameliorated but markers of ER stress (calnexin, grp78) and apoptosis were not reduced by irbesartan. On the other hand, inflammatory cell infiltration in the tubulointerstitium and the glomerulus was significantly attenuated. We conclude that irbesartan reduced renal damage even in a very low dose. The beneficial effects of low dose irbesartan were paralleled by a reduction of blood pressure and inflammation but not by a reduction of ER stress and apoptosis. Thus, sustained endoplasmic reticulum stress in the kidney does not necessarily lead to increased inflammation and tubulointerstitial or glomerular injury.

Keywords: Angiotensin receptor antagonist; Diabetic nephropathy; ER stress; Inflammation; Irbesartan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / therapeutic use*
  • Animals
  • Apoptosis / drug effects
  • Biphenyl Compounds / therapeutic use*
  • Blood Glucose / analysis
  • Blood Pressure / drug effects
  • Diabetic Nephropathies / drug therapy*
  • Endoplasmic Reticulum Stress / drug effects*
  • Inflammation / prevention & control*
  • Irbesartan
  • Kidney / drug effects*
  • Male
  • Rats
  • Smad Proteins / physiology
  • Tetrazoles / therapeutic use*
  • Transforming Growth Factor beta / physiology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Biphenyl Compounds
  • Blood Glucose
  • Smad Proteins
  • Tetrazoles
  • Transforming Growth Factor beta
  • Irbesartan