Effects of endothelin receptor antagonists on the progression of diabetic nephropathy.
BACKGROUND
Diabetic nephropathy is the leading cause of end-stage renal disease in European countries and is associated with an enhanced renal synthesis of endothelin (ET)-1. ETs are - beside their potent vasoconstrictor properties - very potent profibrotic acting paracrine hormones especially in the kidney.


METHODS
We analyzed in rats with streptozotocin-induced diabetes the effects of an ETA-type (ETA) receptor antagonist (LU 135252) in comparison to a combined ETA/ETB receptor antagonist (LU 224332) on the expression of interstitial and glomerular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry using a computer-aided image analysis system. Global glomerular matrix deposition was analyzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excretion. The diabetic rats were treated for 36 weeks.


RESULTS
Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive material within the glomeruli. The expression of glomerular fibronectin and type IV collagen was increased 36 weeks after induction of diabetes. The overexpression of these two matrix proteins within the glomeruli of diabetic rats was completely abolished by both ET receptor antagonists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treatment.


CONCLUSIONS
The present study indicates that ETA receptor antagonists as well as combined ETA/ETB receptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyperglycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new approach in the treatment of diabetic nephropathy.
Department of Nephrology, Charité, Humboldt University of Berlin, Germany. berthold.hocher@rz.hu-berlin.de
B
B
Hocher
A
A
Schwarz
D
D
Reinbacher
J
J
Jacobi
A
A
Lun
F
F
Priem
C
C
Bauer
H H
HH
Neumayer
M
M
Raschack
D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D005353:Fibronectins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D010666:Phenylpropionates / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D065128:Endothelin Receptor Antagonists; D005353:Fibronectins; C113044:LU 224332; D007797:Laminin; D010666:Phenylpropionates; D011422:Propionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C107831:darusentan; D003094:Collagen