DM, Inscho EW.Immunosuppression preserves renal autoregulatory function and microvascular P2X1 receptor reactivity in ANG II-hypertensive rats. Am J Physiol Renal Physiol 304: F801-F807, 2013. First published December 26, 2012 doi:10.1152/ajprenal.00286.2012.-Autoregulation is critical for protecting the kidney against arterial pressure elevation and is compromised in some forms of hypertension. Evidence indicates that activated lymphocytes contribute importantly to cardiovascular injury in hypertension. We hypothesized that activated lymphocytes contribute to renal vascular dysfunction by impairing autoregulation and P2X1 receptor signaling in ANG II-infused hypertensive rats. Male Sprague-Dawley rats receiving ANG II infusion were treated with a lymphocyte proliferation inhibitor, mycophenolate mofetil (MMF) for 2 wk. Autoregulation was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. ANG II-treated rats exhibited impaired autoregulation. At the single vessel level, pressure-mediated afferent arteriolar vasoconstriction was significantly blunted (P Ͻ 0.05 vs. control rats). At the whole kidney level, renal blood flow passively decreased as renal perfusion pressure was reduced. MMF treatment did not alter the ANG II-induced hypertensive state; however, MMF did preserve autoregulation. The autoregulatory profiles in both in vitro or in vivo settings were similar to the responses from control rats despite persistent hypertension. Autoregulatory responses are linked to P2X1 receptor activation. Accordingly, afferent arteriolar responses to ATP and the P2X1 receptor agonist ␤,␥-methylene ATP were assessed. ATP-or ␤,␥-methylene ATP-induced vasoconstriction was significantly attenuated in ANG II-infused hypertensive rats but was normalized by MMF treatment. Moreover, MMF prevented elevation of plasma transforming growth factor-␤1 concentration and lymphocyte and macrophage infiltration in ANG II-infused kidneys. These results suggest that anti-inflammatory treatment with MMF prevents lymphocyte infiltration and preserves autoregulation in ANG II-infused hypertensive rats, likely by normalizing P2X 1 receptor activation. autoregulation; inflammation; renal blood flow; mycophenolate mofetil; lymphocytes; afferent arteriole EFFICIENT RENAL AUTOREGULATORY function is critical for controlling renal perfusion and for maintaining stable glomerular capillary pressure in the face of arterial pressure (AP) fluctuations. Renal autoregulation is accomplished by precise adjustments of preglomerular resistance. A decline in afferent arteriolar autoregulatory efficiency renders downstream glomerular capillaries vulnerable to glomerular capillary hypertension. Prolonged glomerular hypertension can lead to glomerulosclerosis and chronic renal failure. Studies from both hypertensive human subjects and animal models indicate that reduced autoregulatory efficiency can precede renal structural changes, particularly in African Americans (27). This suggests that...

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Previous work shows that a high salt diet (HS) blunts afferent arteriolar (AA) autoregulatory behavior by 83% partly through reactive oxygen species (ROS). Thus, we tested the hypothesis that HS blunts autoregulation by enhancing NADPH‐dependent ROS production. Rats were fed a normal (NS 0.8% NaCl) or HS (8% NaCl) diet for 14 days. A subset of rats, received the NADPH oxidase inhibitor, apocynin (~25mg/kg/day) in the drinking water. Studies were performed in vivo to assess whole kidney autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) when left kidney perfusion pressure (PP) was reduced to ~95mmHg using an adjustable aortic clamp. Decreasing PP significantly reduced RBF in HS rats by 18%, from a baseline of 12.6 ±0.6 to 10.4±0.6 ml/min (n=8) compared to 2% in NS rats (8.3±0.8 to 8.1±0.9 ml/min; n=10; P<.05 vs. HS). Apocynin treatment improved autoregulatory behavior in HS rats with RBF declining by just 8%, from a baseline of 12.5 ±0.5 to 11.6 ±0.5 ml/min (n=11). Similarly, left kidney GFR declined by 27% (457 ± 24 vs. 335 ± 31 μl/min/100gbw; n=8) in HS rats compared to just 5% (496 ±46 vs. 470± 39 μl/min/100gbw; n=10) in NS rats. Apocynin improved GFR autoregulation in HS rats with only a 12% reduction at 95 mmHg (472±39 vs. 417±21 μl/min/100gbw; n=11). These data suggest that NADPH oxidase‐derived ROS impair renal autoregulatory behavior in rats fed a HS diet.Funding: NIH‐HL098135, NIH‐1PO1HL095499