Unexpected effect of angiotensin AT₁receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy

Abstract

Singh P, Deng A, Blantz RC, Thomson SC. Unexpected effect of angiotensin AT1 receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy. Am J Physiol Renal Physiol 296: F1158 -F1165, 2009. First published February 11, 2009 doi:10.1152/ajprenal.90722.2008.-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 glomerular filtration rate (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 the 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-operated rats. In STN, the feedback responses were highly variable and nil, 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. J prox was subtly affected by chronic losartan in sham surgery or STN, after controlling for differences in SNGFR. However, when administered acutely into the early S1 segment, losartan potently suppressed J prox in STN and sham-operated rats alike. Chronic losartan stabilizes the TGF system in remnant kidneys. This cannot be explained by currently known actions of AT 1 receptors but is commensurate with a salutary effect of an intact TGF system on dynamic autoregulation of intraglomerular flow and pressure.proximal tubular reabsorption; glomerulotubular balance; hyperfiltration REDUCING THE NUMBER OF NEPHRONS evokes a response from those that remain (3). One early and notable feature of this response is an increase in single-nephron glomerular filtration rate (SNGFR). From the body's standpoint this increase in SNGFR is adaptive, since it compensates for lost filtration. But from the nephron's standpoint this increase in SNGFR can be maladaptive, since hyperfiltration imposes physical stress on the glomerulus and metabolic stress on the tubule. The latter results from the work required of each remaining nephron to reabsorb most of its increase in filtered sodium, which is necessary for short-term survival. Without this glomerulotubular balance (GTB) the compensatory increase in SNGFR would cause rapidly fatal salt depletion.The mechanism for sensing a loss of nephrons and evoking compensation from the remainder remains a mystery, but the possible explanations can be classified based on a general understanding of how SNGFR is regulated. Wh...

Aberrant Tubuloglomerular Feedback and HIF-1α Confer Resistance to Ischemia after Subtotal Nephrectomy

“…7 We confirmed this finding in the current study and also showed normal tubuloglomerular feedback responses in UN. Furthermore, we have shown that preserving normal tubuloglomerular feedback in STN with losartan diminished the functional resistance of STN.…”

“…Chronic angiotension I receptor blockade was achieved by adding losartan (200 mg/L) to the drinking water. 7 Placebo controls were given a water bottle with no losartan. For HIF induction, CoCl 2 was administered at 30 mg/kg two times a day subcutaneously for 2 days, with the last dose 6 hours before IR.…”

“…We have previously discovered that blocking angiotensin receptors with losartan in STN completely corrected the aberrant tubuloglomerular feedback response. 7 Using an identical protocol, we administered losartan to STN rats and performed micropuncture experiments to confirm the preservation of a normal feedback response pre-and post-IR and test whether this administration would increase the sensitivity to IR. These groups are designated as STN+L and STN+L+IR.…”

“…We have recently observed a lack of normal tubuloglomerular feedback responses in the STN kidney. 7 Tubuloglomerular feedback activation caused by decreased reabsorption by the injured proximal tubule is implicated in the pathogenesis of various forms of AKI. Therefore, the aberrant tubuloglomerular feedback activity observed in STN could influence the susceptibility to filtration failure in AKI.…”

Chronic Kidney Disease

“…Hence, for hyperfiltration to endure, some alteration of the TGF system becomes necessary. When we examined TGF activity at early stages after STN in rats, no TGF response was observed (42). Furthermore, paradoxical restoration of TGF response in STN was observed with angiotensin II blockade, as typically, TGF response is subdued by blocking angiotensin II.…”