Role of the eNOS-NO system in regulating the antiproteinuric effects of VEGF receptor 2 inhibition in diabetes.
Subtle perturbations in intraglomerular VEGF/VEGFR-2 signaling or in the influencing microenvironment can profoundly affect renal function, resulting in the apparently paradoxical observation that VEGF blockade attenuates proteinuria development in experimental diabetes despite exerting the opposite effect under other circumstances. In the present study, we sought to explore the role of eNOS-NO activity in regulating the differential response to VEGF blockade in the diabetic and nondiabetic settings. In a rodent model of accelerated renal injury, the transgenic (mRen-2)27 (Ren-2) rat, VEGFR-2 inhibition with the small molecule vandetanib resulted in an increase in urine protein excretion preceding a subsequent rise in systolic blood pressure. When compared to their normoglycaemic counterparts, diabetic Ren-2 rats exhibited an increase in the renal expression of eNOS and in urinary excretion of nitric oxide (NO) metabolites. In contrast to the heavy proteinuria observed with vandetanib in nondiabetic TGR(mRen-2)27 rats, VEGFR-2 inhibition reduced urine protein excretion in diabetic animals, despite a comparable magnitude of histological injury. However, proteinuria was markedly increased by concomitant treatment of diabetic Ren-2 rats with vandetanib and the nitric oxide synthase inhibitor L-NAME. These observations highlight the pivotal role that the eNOS-NO system plays in regulating the biologic response to VEGF within the glomerulus.
Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 6-151, 61 Queen Street East, Toronto, ON, Canada M5C 2T2.
Andrew
A
Advani
Kim A
KA
Connelly
Suzanne L
SL
Advani
Kerri
K
Thai
Yuan
Y
Zhang
Darren J
DJ
Kelly
Richard E
RE
Gilbert
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000503:physiopathology / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism* / Q000652:urine; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011507:Proteinuria / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000652:urine; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013599:Systole / Q000187:drug effects
D010880:Piperidines; D011799:Quinazolines; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib