Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity.
Recent studies have demonstrated the presence of the (pro)renin receptor (PRR) in the glomerular mesangium and the subendothelial layer of the renal arteries. We hypothesized that diabetes upregulates PRR expression through enhanced angiotensin subtype 1 (AT1) receptor-NADPH oxidase cascade activity. Using real-time polymerase chain reaction, Western blot analysis and immunostaining, we studied renal localization of the PRR in the streptozotocin-induced diabetic rat model and in response to 1 week of treatment with the AT1 receptor blocker valsartan (10 mg kg(-1) day(-1)), the angiotensin AT2 receptor blocker PD123319 (0.5 mg kg(-1) day(-1)) or the NADPH oxidase inhibitor diphenylene iodonium (DPI; 0.5 mg kg(-1) day(-1)) 6 weeks post-induction of diabetes. Both PRR mRNA and protein were expressed constitutively in the kidneys of normal rat renal cortex and medulla, mainly in glomerular mesangium, proximal, distal and collecting tubules. Compared with normal rats (100%), diabetic rats demonstrated an increase in renal PRR mRNA (184%), protein (228%) and immunostaining. Valsartan and DPI prevented the increase in the PRR mRNA (106 and 126%, respectively), protein (97 and 140%, respectively) and immunostaining that was seen in the kidneys of diabetic rats. The AT2 blocker PD123319 did not have significant effects on PRR mRNA (157%) or protein expression (200%) in the kidneys of diabetic rats. These results demonstrate that the PRR is constitutively expressed in renal glomeruli and tubules. Expression of the PRR is upregulated in diabetes via enhancement of AT1 receptor-NADPH oxidase activity.
Siragy
Helmy M
HM
Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1409, USA. hms7a@virginia.edu
Huang
Jiqian
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D000093342:Prorenin Receptor
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D007093:Imidazoles; D009861:Onium Compounds; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D013777:Tetrazoles; C073402:PD 123319; C007517:diphenyleneiodonium; D000068756:Valsartan; D019255:NADPH Oxidases; D014633:Valine; D000093342:Prorenin Receptor