Submitted on October 22, 2008
Revised on February 9, 2009
Accepted on February 9, 2009
DIFFERENTIAL REGULATION OF ANGIOTENSIN-(1-12) IN PLASMA AND CARDIAC TISSUE IN RESPONSE TO BILATERAL NEPHRECTOMY
Carlos M Ferrario1*, Jasmina Varagic2, Javad Habibi3, Sayaka Nagata, Johji Kato4, Mark C. Chappell1, Aaron J. Trask5, Kazuo Kitamura6, Adam T Whaley-Connell, and James R Sowers7
1 Wake Forest University School of Medicine
2 Wake Forest University
3 University of Missouri
4 University of Miyazaki Faculty of Medicine, Japan
5 Nationwide Children's Hospital
6 Miyazaki University
7 University of Missouri - Columbia
* To whom correspondence should be addressed. E-mail: cferrari{at}wfubmc.edu.
We examined the effects of 48 h bilateral nephrectomy on plasma and cardiac tissue expression of angiotensin (Ang)-(1-12) [Ang-(1-12)], Ang I, and Ang II of adult WKY to evaluate functional changes induced by removal of renal renin. The goal was to uncover additional evidence for an alternate role of Ang-(1-12) in forming Ang peptides independent of renal renin. The anephric state caused divergent effects on circulating and cardiac Ang-(1-12), Ang I, and Ang II content since the plasma levels of the peptides decreased, but increased markedly in the heart of nephrectomized WKY rats compared to sham-operated controls. A 34% decrease in plasma Ang-(1-12) levels post-nephrectomy was associated with a 78% and 66% decrease in plasma Ang I and Ang II, respectively (p < 0.05 versus sham). In contrast, cardiac content of Ang-(1-12) in anephric rats averaged 276 ± 24 fmol/mg compared to 144 ± 20 fmol/mg in controls (p < 0.005). Cardiac Ang I and Ang II values averaged 300 ± 15 fmol/mg and 62 ± 7 fmol/mgm, respectively in anephric WKY rats compared to 172 ± 8 fmol/mg for Ang I and 42 ± 4 fmol/mg for Ang II in sham rats (p < 0.001). Quantitative immunofluorescent assessment revealed significant increases in the average gray intensity values for cardiac angiotensinogen, Ang I, Ang II, and AT1 receptors in WKY rats post-nephrectomy. Very faint renin fluorescence in cardiac tissue sections that was not changed by nephrectomy was associated, in contrast, with an 80% decrease in cardiac angiotensinogen mRNA. These changes were accompanied by significant increases in the expression of p47phox and Rac1 NADPH oxidase regulatory subunits, and Nox4 isoforms. We conclude that Ang-(1-12) may act as a functional precursor for the formation of angiotensin peptides in the absence of circulating renin.
