ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

Diabetologia. 2003 Jun;46(6):856-68. doi: 10.1007/s00125-003-1106-8. Epub 2003 Jun 11.

Abstract

Aims/hypothesis: It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats.

Methods: Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-beta, ET-1, PDGF-AB, fibronectin, desmin and alpha-smooth muscle cell actin was investigated by immunohistochemistry.

Results: The mean number of podocytes per glomerulus was lower (86+/-17 vs. 138+/-25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET(A)-RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27(kip1) positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-beta. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment.

Conclusion/interpretation: Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET(A)-RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET(A)-receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetic Nephropathies / pathology*
  • Diabetic Nephropathies / prevention & control*
  • Disease Models, Animal
  • Endothelin Receptor Antagonists*
  • Hypertrophy
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / pathology
  • Kidney Tubules / cytology
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Male
  • Phenylpropionates / pharmacology
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Endothelin Receptor Antagonists
  • Phenylpropionates
  • Pyrimidines
  • darusentan