Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 298, Issue 1, Pages F37-F48Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00519.2009
Keywords
afferent arteriole; juxtamedullary nephron; db/db mouse; angiotensin-converting enzyme; serine protease; angiotensinogen; angiotensin-converting enzyme 2
Categories
Funding
- National Institutes of Health (NIH) [DK62003, P20 RR018766, P20RR017659, HL-56973]
- American Heart Association (AHA) [0715445B]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR017659, P20RR018766] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL056973, R29HL056973] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R56DK062003, R01DK062003, R01DK072408] Funding Source: NIH RePORTER
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Park S, Bivona BJ, Kobori H, Seth DM, Chappell MC, Lazartigues E, Harrison-Bernard LM. Major role for ACE-independent intrarenal ANG II formation in type II diabetes. Am J Physiol Renal Physiol 298: F37-F48, 2010. First published October 21, 2009; doi:10.1152/ajprenal.00519.2009.-Combination therapy of angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.1 +/- 0.8 vs. 9.2 +/- 2.1 arbitrary fluorescence units (AFU).mg(-1).min(-1)] and intensity of immunohistochemical staining were significantly reduced and ACE2 protein activity (16.7 +/- 3.2 vs. 7.2 +/- 2.4 AFU.mg(-1).min(-1)) and intensity elevated, kidney ANG I (113 +/- 24 vs. 110 +/- 45 fmol/g) and ANG II (1,017 +/- 165 vs. 788 +/- 99 fmol/g) levels were not different between diabetic and control mice. Afferent arteriole vasoconstriction due to conversion of ANG I to ANG II was similar in magnitude in kidneys of diabetic (-28 +/- 3% at 1 mu M) and control (-23 +/- 3% at 1 mu M) mice; a response completely inhibited by AT1 receptor blockade. In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by intrarenal conversion of ANG I to ANG II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys. In conclusion, there is a switch from ACE-dependent to serine protease-dependent ANG II formation in the type II diabetic kidney. Pharmacological targeting of these serine protease-dependent pathways may provide further protection from diabetic renal vascular disease.
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