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


CONCLUSIONS
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.
Gross
M-L
ML
Department of Pathology, University of Heidelberg, Im Neuenheimer Feld, 69120 Heidelberg, Germany. Marie-Luise_Gross@med.uni-heidelberg.de
El-Shakmak
A
A
Szábó
A
A
Koch
A
A
Kuhlmann
A
A
Münter
K
K
Ritz
E
E
Amann
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan