Normalizing NADPH oxidase contributes to attenuating diabetic nephropathy by the dual endothelin receptor antagonist CPU0213 in rats.
OBJECTIVE
NADPH oxidase(NOX) is the main source of reactive oxygen species (ROS) in diabetic nephropathy (DN). Activation of NOX could be mediated via endothelin A (ET(A)R) and B receptors (ET(B)R) of the endothelin (ET) system. Thus, CPU0213, a dual ET receptor antagonist, was expected to attenuate DN by suppressing NOX.


METHODS
Diabetes was produced in male Sprague-Dawley rats 8 weeks after a single injection of streptozotocin (STZ), and treatment with CPU0213 was initiated in the last 4 weeks. Rat mesangial cells (MCs) were incubated with 30 mM glucose for 48 h supplemented with CPU0213 or the NOX inhibitors apocynin and diphenyleneiodonium.


RESULTS
After 8 weeks of hyperglycemia, abnormal renal function was associated with oxidative stress and an increased renal weight index in STZ-treated rats. Additionally, upregulation of NOX subunits and the ET system was found in diabetic rats and MCs treated with 30 mM glucose and suppressed by CPU0213 or NOX inhibitors. Except for blood glucose, CPU0213 markedly suppressed these abnormalities in DN.


CONCLUSIONS
Upregulation of NOX is associated with upregulation of the ET pathway in the pathology of DN. The dual ET receptor antagonist (ET(A)R and ET(B)R) CPU0213 effectively normalized renal function in DN by suppressing NOX.
Xu
Ming
M
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
Dai
De-Zai
DZ
Dai
Yin
Y
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000201:enzymology*; D065128:Endothelin Receptor Antagonists; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*
C513821:CPU0213; D065128:Endothelin Receptor Antagonists; D011720:Pyrazoles; D017466:Receptors, Endothelin; D019255:NADPH Oxidases