Renal Autoregulation in Health and Disease

Abstract

Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.

Renal Handling of Ketones in Response to Sodium–Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes

“…proximal sodium absorption delivers an excess of sodium (and chloride) to the macula densa, thereby triggering the release of vasoconstrictive molecules (adenosine, prostaglandin H2, and thromboxane A2) and vasoconstriction of the afferent glomerular arterioles (24). It has been argued that this resetting of the tubuloglomerular feedback is the likely mechanism underlying the acute decrement in GFR observed in patients with type 1 diabetes (25).…”

Beware: The femoral haemodialysis catheter – a surgeon’s perspective

“…This equates to an increase in iliac vein outflow of approximately 550 mL/min in a 70 kg adult male. [16] In the presence of unrecognised upstream perivascular fibrosis and reduced venous compliance, a functional stenosis may only be unmasked upon reperfusion, potentially leading to allograft congestion and early renal vein thrombosis.…”

Do You Want to Ditch Sodium? Meet Nitric Oxide Synthase 1β at the Macula Densa

“…[2][3][4] Several organs, including the kidney, participate in whole-body sodium homeostasis and BP regulation. 5 The importance of the kidney in BP regulation is supported by renal transplantation studies in humans and rodents. 6,7 The inability of the kidney to excrete a sodium load would result in a positive sodium balance, an increase in BP, and eventually, hypertension.…”

“…5,8 This is afforded by myogenic and macula densa (MD) tubuloglomerular feedback responses. Several vasoactive agents have been proposed to mediate or modulate tubuloglomerular feedback, including nitric oxide and angiotensin II.…”

“…Several vasoactive agents have been proposed to mediate or modulate tubuloglomerular feedback, including nitric oxide and angiotensin II. 5,8 Neuronal nitric oxide synthase (nNOS) is expressed in the MD, and direct blockade by specific inhibitors increases tubuloglomerular feedback. 9 However, the inhibition of nitric oxide synthesis modulates but does not impair the myogenic vasoconstriction of the afferent arteriole in spontaneously hypertensive rats.…”