Assessment of renal autoregulation

Abstract

The kidney displays highly efficient autoregulation so that under steady-state conditions renal blood flow (RBF) is independent of blood pressure over a wide range of pressure. Autoregulation occurs in the preglomerular microcirculation and is mediated by two, perhaps three, mechanisms. The faster myogenic mechanism and the slower tubuloglomerular feedback contribute both directly and interactively to autoregulation of RBF and of glomerular capillary pressure. Multiple experiments have been used to study autoregulation and can be considered as variants of two basic designs. The first measures RBF after multiple stepwise changes in renal perfusion pressure to assess how a biological condition or experimental maneuver affects the overall pressure-flow relationship. The second uses time-series analysis to better understand the operation of multiple controllers operating in parallel on the same vascular smooth muscle. There are conceptual and experimental limitations to all current experimental designs so that no one design adequately describes autoregulation. In particular, it is clear that the efficiency of autoregulation varies with time and that most current techniques do not adequately address this issue. Also, the time-varying and nonadditive interaction between the myogenic mechanism and tubuloglomerular feedback underscores the difficulty of dissecting their contributions to autoregulation. We consider the modulation of autoregulation by nitric oxide and use it to illustrate the necessity for multiple experimental designs, often applied iteratively.

Ca2+ entry following P2X receptor activation induces IP3 receptor‐mediated Ca2+ release in myocytes from small renal arteries

“…In contrast, the results of more recent experiments conducted on isolated pulmonary artery myocytes suggested that IP3-releasable and caffeine-releasable calcium stores are virtually completely separate (Janiak et al, 2001). A similar conclusion was made from the experiments performed on in intact precapillary vessels, where agonistinduced [Ca 2+ ]i oscillations were insensitive to the combined action of caffeine and ryanodine (Borisova et al, 2009 We tested our hypothesis that Ca 2+ entry following P2X activation may induce IP3R-mediated Ca 2+ release on RVSMCs, because: (i) P2X receptors mediate sympathetic control and autoregulation of the renal circulation (Malpas and Leonard, 2000;Nishiyama et al, 2000;Bell et al, 2003;Inscho et al, 2003;Cupples and Braam, 2007;Guan et al, 2007a;Surprenant and North, 2009); and (ii) RVSMCs express functional monomeric P2X1 and heteromeric P2X1/4 receptors (Harhun et al, 2010).We found that depolarization of RVSMC induced by selective stimulation of P2X receptors with ab-meATP triggers Ca 2+ release from sub-plasmalemmal SR enriched with IP3Rs but poor in RyRs, similar to direct stimulation of IP3Rs by uniform cell-wide release of IP3 from its 'caged' precursor. The ab-meATP-induced SPCU was significantly reduced by block of VGCCs or depletion of the intracellular calcium stores, indicating that activation of P2X receptors in RVSMCs recruits both voltage-gated Ca 2+ entry and the SR Ca 2+ release to intracellular Ca 2+ mobilization.…”

“…Although M3 receptors are linked to a Gq/11/PLC/IP3/Ca 2+ signalling pathway, we hypothesized that in contrast to cardiac muscle, excitation-contraction (E-C) coupling in smooth muscle occurs by Ca 2+ entry through VGCCs, which evokes IP3R-mediated Ca 2+ release via CICR mechanism. This hypothesis needs to be tested in vascular myocytes regulated by ionotropic receptors, which are not coupled to the Gq/11-GTP/PLC/IP3 system.Taking into account the importance of ionotropic P2X receptors (Burnstock, 2007;Surprenant and North, 2009) in the regulation of renal circulation (Malpas and Leonard, 2000;Inscho et al, 2003;Cupples and Braam, 2007;Guan et al, 2007a), we tested our hypothesis on RVSMCs, which, as we have recently demonstrated, express functional monomeric P2X1 and heteromeric P2X1/4 receptors (Harhun et al, 2010). We found that depolarization of RVSMCs following P2X receptor activation induces IP3R-mediated Ca 2+ release from sub-plasmalemmal ('junctional') sarcoplasmic reticulum (jSR), which is activated mainly by Ca 2+ influx through VGCCs.…”

“…On being released by apical macula densa cells in response to an increase in NaCl concentration in the distal tubular fluid (Bell et al, 2003), ATP triggers P2X receptor-mediated vasoconstriction of afferent arterioles (Inscho et al, 2003), thus decreasing RBF and glomerular filtration rate. This tubuloglomerular feedback mechanism (Nishiyama et al, 2000;Guan et al, 2007a;Surprenant and North, 2009) and myogenic mechanism are two important components of renal autoregulation (Cupples and Braam, 2007).The respective role of RyRs and IP3Rs in smooth muscle contraction is an area of active investigation. Although RyRs and IP3Rs are both Ca 2+ -sensitive and can activate each other via CICR mechanism, leading to an all-or-none regenerative response, graded Ca 2+ signals have been reported to be evoked by increasing stimuli targeting RyRs (Isenberg and Han, 1994) or IP3Rs (Bootman et al, 1994).…”

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

“…32 The renal autoregulatory response is coordinated by two mechanisms: myogenic response and tubulo-glomerular feedback. 33 On the basis of the results of our experiments in DS rats, ARB seems to improve the renal autoregulatory response in parallel with endothelial function. The endothelium has a central role in early functional adaptations to hypertension.…”

Renal Oxygenation in Clinical Acute Kidney Injury

“…Th us, furose mide decreased renal O 2 Ex and improved renal oxygenation as renal blood fl ow was not signifi cantly aff ected by the diuretic. Interestingly, GFR decreased by 12 % with furosemide, which could be explained by an increased delivery of sodium to the distal tubules activating the tubuloglomerular feedback mechanism, eventu ally inducing a constriction of the aff erent arterioles and a decrease in GFR [17]. Th is mechanism could explain the fi ndings of Lassnigg et al, who demonstrated in low-risk cardiac surgery patients with normal renal function that furosemide lowered creatinine clearance postoperatively [18].…”