Submitted on December 2, 2008
Revised on February 9, 2009
Accepted on February 9, 2009
Unexpected effect of angiotensin AT-1 receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy
Prabhleen Singh1, Aihua Deng2, Roland C Blantz3, and Scott C. Thomson4*
1 University of California, San Diego
2 University of California
3 UCSD & VASDHS
4 University of California and VA Medical Center
* To whom correspondence should be addressed. E-mail: sthomson{at}ucsd.edu.
After subtotal nephrectomy (STN), the remaining nephrons engage in hyperfiltration, which may be facilitated by a reduced sensitivity of the tubuloglomerular feedback (TGF) response to increased distal delivery. However, a muted TGF response would contradict the notion of remnant kidney as a prototype of Angiotensin II (Ang II) excess, since Ang II normally sensitizes the TGF response and stimulates proximal reabsorption. We examined the role of Ang II as a modulator of TGF and proximal reabsorption in 7 days after STN in male rats. Single nephron GFR (SNGFR) and proximal reabsorption (Jprox) were measured in late proximal collections while perfusing Henle's loop for minimal and maximal TGF stimulation in rats treated with angiotensin type 1 (AT1) receptor blocker, losartan, or placebo in drinking water for 7 days. Perfusion of Henle's loop yielded a robust TGF response in sham. In STN, the feedback responses were highly variable and naught, on average. Paradoxical TGF responses to augmented late proximal flow were confirmed in SNGFR measurements from the early distal nephron. Chronic losartan treatment normalized the average TGF response without reducing the variability. Jprox was subtly affected by chronic losartan in sham or STN, after controlling for differences in SNGFR. However, when administered acutely into the early S1 segment, losartan potently suppressed Jprox in STN and shams alike. Chronic losartan stabilizes the TGF system in remnant kidneys. This cannot be explained by currently known actions of AT1 receptors, but is commensurate with a salutary effect of an intact TGF system on dynamic autoregulation of intraglomerular flow and pressure.
