Mysteries of Renal Autoregulation

Abstract

A utoregulation is an important renal regulatory mechanism that provides an important protective role in glomerular hemodynamics. 1 The phenomenon of autoregulatory behavior has been recognized for many decades, but a clear understanding of the underlying mechanisms involved in mediating resistance adjustments remains to be established. As illustrated in Figure 1, pressure-mediated autoregulatory behavior operates by recognizing a change in renal perfusion pressure, or renal vascular transmural pressure, and initiating induction of autoregulatory resistance changes intended to stabilize renal blood flow and/or glomerular filtration rate. The net result is that renal blood flow and glomerular filtration rate remain relatively stable over a wide range of renal perfusion pressures. Autoregulatory behavior is exquisitely sensitive in healthy normal kidneys but significantly less efficient in pathological settings, such as diabetes mellitus and some forms of hypertension. Complete loss of autoregulatory control results in renal blood flow that behaves more passively, thus increasing variability and rendering flow more directly determined by renal perfusion pressure. 1,2 Whole kidney autoregulation reflects regulatory input from the myogenic and tubuloglomerular feedback mechanisms at the very least. [3][4][5][6][7] Recently, contributions of a third and possibly a fourth mechanism have been suggested. 6,7 Consequently, with continued study, the mechanisms underlying renal autoregulatory resistance adjustments are slowly becoming clearer. In addition to the P1 receptor hypothesis put forth to explain signal transduction for tubuloglomerular feedback-dependent resistance changes, we have explored the hypothesis that pressure-mediated autoregulatory responses are mediated by extracellular ATP and activation of P2X 1 receptors. 3,8,9 Conclusive identification of the signaling molecules that mediate autoregulation remains a point of debate, but it appears clear that the release of a purine-based moiety is required for autoregulatory adjustments in afferent arteriolar resistance. 3-5,8 -10 This review tries to focus on the new and current questions that need resolution regarding the P2 receptor hypothesis and how the tubuloglomerular feedback (TGF) system overlaps with those questions. For a more detailed discussion and review of the mechanisms of TGF and myogenic contributions to autoregulatory behavior, the reader is referred to several recent and excellent reviews that dwell more on the relative contributions of both systems to overall autoregulation.

The renin-angiotensin system and the third mechanism of renal blood flow autoregulation

“…ANG II directly constricts preglomerular and postglomerular vessels (30,66), thereby potentially changing filtered NaCl load, which in turn will change distal load including macula densa load, i.e., the tubular TGF signal (49). Moreover, ANG II appears to be involved in the paracrine signaling of TGF as a cofactor to adenosine and ATP (21,50). ANG II also increases NaCl resorption; thus distal NaCl load is altered even at constant filtered load.…”

“…5). As recently reviewed (21,50), the TGF (assessed by micropuncture techniques) is abolished in mice lacking either adenosine type 1 receptors or P2x1 purinergic receptors, pointing at adenosine and ATP as required constituents of the paracrine signaling pathway. Remarkably, the TGF response was also found largely absent in mice with deletions of ANG II type 1 receptors or ACE (50).…”

Mechanism of impaired afferent arteriole myogenic response in Dahl salt-sensitive rats: role of 20-HETE

“…And the effect of P2X receptor activation is in turn mediated by 20-HETE (13). Furthermore, inhibitors of 20-HETE formation and action blunt the effect of and the myogenic response in vitro and renal autoregulation in vivo (18,36), suggesting that 20-HETE may be a second messenger of the myogenic response downstream from ATP.…”

“…RENAL BLOOD FLOW is highly regulated, with at least three intrinsic renal mechanisms contributing to its fine control: myogenic response, tubuloglomerular feedback (TGF), and connecting tubule glomerular feedback (CTGF) (5,13,27). In the myogenic response, the afferent arteriole (Af-Art) constricts in response to increases in perfusion pressure.…”

A Multicellular Vascular Model of the Renal Myogenic Response

“…Indeed, multiscale modeling that spans processes ranging from the subcellular up to the organ level is required to elucidate clinical and experimental findings such as the effects of integrins [31,32], epithelial sodium channels (ENaCs) [33,34], angiotensin II (AngII) [35][36][37][38], nitric oxide (NO) [39,40], and an array of other vasomodulators [41][42][43][44], or the pathophysiology associated with certain chronic conditions such as hypertension [45,46], diabetes mellitus [47,48], or chronic kidney disease [49,50]. Most of these previous studies have used simple compartmental models (Windkessels), ordinary or partial differential equations, and more recently, probabilistic methods for reproducing renal vascular networks [28].…”