Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy

1 Hypertension and Vascular Research Center and Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; 2 Diabetes Cardiovascular Center, University of Missouri-Columbia School of Medicine, and Harry S. Truman VA Medical Center, Columbia, Missouri; and 3 Circulatory and Body Fluid Regulation, Faculty of Medicine University of Miyazaki, Kihara, Kiyotake, Miyazaki, Japan Submitted 22 October 2008 ; accepted in final form 9 February 2009 We examined the effects of 48 h bilateral nephrectomy on plasma and cardiac tissue expression of angiotensin-(1-12) [ANG-(1-12)], ANG I, and ANG II in adult Wistar-Kyoto rats to evaluate functional changes induced by removing renal renin. The goal was to expand the evidence of ANG-(1-12) being an alternate renin-independent, angiotensin-forming substrate. Nephrectomy yielded divergent effects on circulating and cardiac angiotensins. Significant decreases in plasma ANG-(1-12), ANG I, and ANG II levels postnephrectomy accompanied increases in cardiac ANG-(1-12), ANG I, and ANG II concentrations compared with controls. Plasma ANG-(1-12) decreased 34% following nephrectomy, which accompanied 78 and 66% decreases in plasma ANG I and ANG II, respectively ( P < 0.05 vs. controls). Contrastingly, cardiac ANG-(1-12) in anephric rats averaged 276 ± 24 fmol/mg compared with 144 ± 20 fmol/mg in controls ( P < 0.005). Cardiac ANG I and ANG II values were 300 ± 15 and 62 ± 7 fmol/mg, respectively, in anephric rats compared with 172 ± 8 fmol/mg for ANG I and 42 ± 4 fmol/mg for ANG II in controls ( P < 0.001). Quantitative immunofluorescence revealed significant increases in average grayscale density for cardiac tissue angiotensinogen, ANG I, ANG II, and AT 1 receptors of WKY rats postnephrectomy. Faint staining of cardiac renin, unchanged by nephrectomy, was associated with an 80% decrease in cardiac renin mRNA. These changes were accompanied by significant increases in p47 phox , Rac1, and Nox4 isoform expression. In conclusion, ANG-(1-12) may be a functional precursor for angiotensin peptide formation in the absence of circulating renin. renin; angiotensinogen; angiotensin II; blood pressure Address for reprint requests and other correspondence: C. M Ferrario, The Hypertension and Vascular Research Center, Wake Forest Univ. School of Medicine, Winston-Salem, NC 27157 (e-mail: cferrari{at}wfubmc.edu )