Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.

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Renal Autoregulation in Health and Disease

Physiological Reviews ◽

10.1152/physrev.00042.2012 ◽

2015 ◽

Vol 95 (2) ◽

pp. 405-511 ◽

Cited By ~ 200

Author(s):

Mattias Carlström ◽

Christopher S. Wilcox ◽

William J. Arendshorst

Keyword(s):

Intracellular Signaling ◽

Transient Receptor Potential ◽

Trp Channels ◽

Tubuloglomerular Feedback ◽

Free Calcium ◽

Myogenic Response ◽

Renal Vasculature ◽

Renal Autoregulation ◽

Positive Balance ◽

Health And Disease

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 ([Ca2+]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca2+]ioccurs predominantly by Ca2+influx through L-type voltage-operated Ca2+channels (VOCC). Increased [Ca2+]iactivates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca2+from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca2+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.

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Tubuloglomerular feedback, renal autoregulation, and renal protection

10.1093/med/9780199592548.003.0209 ◽

2015 ◽

Cited By ~ 1

Author(s):

Karlhans Endlich ◽

Rodger Loutzenhiser

Keyword(s):

Blood Flow ◽

Glomerular Filtration Rate ◽

Filtration Rate ◽

Essential Role ◽

Vascular Tone ◽

Systolic Pressure ◽

Tubuloglomerular Feedback ◽

Renal Protection ◽

Reduced Pressure ◽

Renal Autoregulation

Vascular tone of glomerular blood vessels is controlled dynamically in response to a number of stimuli of which tubuloglomerular feedback and blood flow (and glomerular filtration rate) autoregulation are the most prominent. Both tubuloglomerular feedback- and myogenic-mediated pre-glomerular vasoconstriction are important in the response to reduced pressure. The renal myogenic mechanism, which has the potential to adjust steady-state tone in response to the oscillating systolic pressure signal, additionally plays an essential role in protecting the kidney from the damaging effects of hypertension.

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Aging Impairs Renal Autoregulation in Mice

Hypertension ◽

10.1161/hypertensionaha.119.13588 ◽

2020 ◽

Vol 75 (2) ◽

pp. 405-412 ◽

Cited By ~ 2

Author(s):

Jin Wei ◽

Jinxiu Zhu ◽

Jie Zhang ◽

Shan Jiang ◽

Larry Qu ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Myogenic Response ◽

Renal Autoregulation ◽

Integrin Α5 ◽

Aging Kidney

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

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Renal autoregulation: models combining tubuloglomerular feedback and myogenic response

AJP Renal Physiology ◽

10.1152/ajprenal.1987.252.4.f768 ◽

1987 ◽

Vol 252 (4) ◽

pp. F768-F783 ◽

Cited By ~ 9

Author(s):

K. Aukland ◽

A. H. Oien

Keyword(s):

Arterial Pressure ◽

Glomerular Filtration ◽

Flow Rate ◽

Tubuloglomerular Feedback ◽

Myogenic Response ◽

Lower Range ◽

Renal Autoregulation ◽

Tubular System ◽

Single Nephron ◽

Tubular Flow

As shown previously, autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) at varying arterial pressure may result from a myogenic response (MR) acting to maintain wall tension in each preglomerular vessel segment. We now combine MR with tubuloglomerular feedback (TGF) responding to distal tubular flow rate. The model consists of preglomerular and postglomerular resistances, glomerular filtration, and a tubular system. TGF acting on preglomerular resistance with parameters that mimic responses to single nephron distal tubular flow rate in rats and dogs failed to account for the autoregulation of RBF and GFR observed experimentally. Good autoregulation was obtained by adding preglomerular MR. In this combination, TGF is activated mainly in the lower range of autoregulation. Addition of mechanisms that increase postglomerular resistance or increase the glomerular filtration coefficient at reduced arterial pressure impairs RBF autoregulation, whereas GFR autoregulation is only slightly improved. TGF regulation of pre- and postglomerular resistance in the same direction seems compatible with good autoregulation only when combined with a preglomerular myogenic mechanism.

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Renal Manifestations of Covid-19: Physiology and Pathophysiology

Journal of Clinical Medicine ◽

10.3390/jcm10061216 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1216

Author(s):

Zaher Armaly ◽

Safa Kinaneh ◽

Karl Skorecki

Keyword(s):

Viral Replication ◽

Virus Disease ◽

Multiorgan Failure ◽

Critical Role ◽

Kidney Injury ◽

Small Sample ◽

Renal Physiology ◽

High Morbidity ◽

Enzymatic Production ◽

High Incidence

Corona virus disease 2019 (COVID-19) imposes a serious public health pandemic affecting the whole world, as it is spreading exponentially. Besides its high infectivity, SARS-CoV-2 causes multiple serious derangements, where the most prominent is severe acute respiratory syndrome as well as multiple organ dysfunction including heart and kidney injury. While the deleterious impact of SARS-CoV-2 on pulmonary and cardiac systems have attracted remarkable attention, the adverse effects of this virus on the renal system is still underestimated. Kidney susceptibility to SARS-CoV-2 infection is determined by the presence of angiotensin-converting enzyme 2 (ACE2) receptor which is used as port of the viral entry into targeted cells, tissue tropism, pathogenicity and subsequent viral replication. The SARS-CoV-2 cellular entry receptor, ACE2, is widely expressed in proximal epithelial cells, vascular endothelial and smooth muscle cells and podocytes, where it supports kidney integrity and function via the enzymatic production of Angiotensin 1-7 (Ang 1-7), which exerts vasodilatory, anti-inflammatory, antifibrotic and diuretic/natriuretic actions via activation of the Mas receptor axis. Loss of this activity constitutes the potential basis for the renal damage that occurs in COVID-19 patients. Indeed, several studies in a small sample of COVID-19 patients revealed relatively high incidence of acute kidney injury (AKI) among them. Although SARS-CoV-1 -induced AKI was attributed to multiorgan failure and cytokine release syndrome, as the virus was not detectable in the renal tissue of infected patients, SARS-CoV-2 antigens were detected in kidney tubules, suggesting that SARS-CoV-2 infects the human kidney directly, and eventually induces AKI characterized with high morbidity and mortality. The mechanisms underlying this phenomenon are largely unknown. However, the fact that ACE2 plays a crucial role against renal injury, the deprivation of the kidney of this advantageous enzyme, along with local viral replication, probably plays a central role. The current review focuses on the critical role of ACE2 in renal physiology, its involvement in the development of kidney injury during SARS-CoV-2 infection, renal manifestations and therapeutic options. The latter includes exogenous administration of Ang (1-7) as an appealing option, given the high incidence of AKI in this ACE2-depleted disorder, and the benefits of ACE2/Ang1-7 including vasodilation, diuresis, natriuresis, attenuation of inflammation, oxidative stress, cell proliferation, apoptosis and coagulation.

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Nitric oxide mediates anomalous tubuloglomerular feedback in rats fed high-NaCl diet after subtotal nephrectomy

AJP Renal Physiology ◽

10.1152/ajprenal.00066.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. F223-F230 ◽

Cited By ~ 4

Author(s):

Scott C. Thomson

Keyword(s):

Nitric Oxide ◽

Tubuloglomerular Feedback ◽

Cross Term ◽

Nitric Oxide Signaling ◽

Subtotal Nephrectomy ◽

Single Nephron ◽

Nos Inhibitor ◽

Tubular Flow ◽

Fluid Collections ◽

Distal Delivery

Tubuloglomerular feedback (TGF) responses become anomalous in rats fed high-NaCl diet after subtotal nephrectomy (STN), such that stimulating TGF causes single nephron GFR (SNGFR) to increase rather than decrease. Micropuncture experiments were performed to determine whether this anomaly results from heightened nitric oxide response to distal delivery, which is a known mechanism for resetting TGF, or from connecting tubule TGF (cTGF), which is a novel amiloride-inhibitable system for offsetting TGF responses. Micropuncture was done in Wistar Froemter rats fed high-NaCl diet (HS) for 8–10 days after STN or sham nephrectomy. TGF was manipulated by orthograde microperfusion of Henle’s loop with artificial tubular fluid with or without NOS inhibitor, LNMMA, or the cell-impermeant amiloride analog, benzamil. SNGFR was measured by inulin clearance in tubular fluid collections from the late proximal tubule. TGF responses were quantified as the increase in SNGFR that occurred when the perfusion rate was reduced from 50 to 8 nl/min in STN or 40 to 8 nl/min in sham animals. The baseline TGF response was anomalous in STN HS (−4 ± 3 vs 14 ± 3 nl/min, P < 0.001). TGF response was normalized by perfusing STN nephron with LNMMA (14 ± 3 nl/min, P < 0.005 for ANOVA cross term) but not with benzamil (−3 ± 4 nl/min, P = 0.4 for ANOVA cross term). Anomalous TGF occurs in STN HS due to heightened effect of tubular flow on nitric oxide signaling, which increases to the point of overriding the normal TGF response. There is no role for cTGF in this phenomenon.

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Congenital heart defects and pregnancy: current view on the mechanisms of placental adaptation to circulatory hypoxia

Voprosy ginekologii akušerstva i perinatologii ◽

10.20953/1726-1678-2020-6-70-82 ◽

2020 ◽

Vol 19 (6) ◽

pp. 70-82

Author(s):

L.A. Rudyuk ◽

◽

O.S. Reshetnikova ◽

Keyword(s):

Pregnant Women ◽

Congenital Heart Defects ◽

Congenital Heart ◽

Heart Defects ◽

Preventive Therapy ◽

Health Improvement ◽

Current View ◽

Compensatory Mechanisms ◽

Circulatory Hypoxia ◽

Fetoplacental Complex

In this review, we perform clinical and morphological analysis of the mechanisms underlying adaptation of the human placenta to hypoxia in the fetoplacental complex in pregnant women with congenital heart defects (CHDs). We assessed specific characteristics of macroscopic and microscopic structure of the placenta in women with this extragenital pathology. We descried morphological involutive dystrophic and compensatory mechanisms that develop in the placenta of women with impaired hemodynamics. We proposed molecular markers, whose investigation will clarify functional state of the placental barrier and ways of remodeling vascular-stromal components of the villous chorion. Potential risks associated with circulatory hypoxia in the mother-placenta-fetus system should be taken into account in the management of pregnant women with CHDs. Detection of placental maladaptation signs in mothers with CHDs will help to identify the risk group of newborns, organize preventive therapy, prophylaxis of diseases, health improvement, and treatment of newborns. Key words: compensatory and adaptive processes, hypoxia, immunohistochemistry, morphology, placenta

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Tubuloglomerular feedback control of distal fluid delivery: effect of extracellular volume

AJP Renal Physiology ◽

10.1152/ajprenal.1986.250.6.f1024 ◽

1986 ◽

Vol 250 (6) ◽

pp. F1024-F1032 ◽

Cited By ~ 9

Author(s):

L. C. Moore ◽

J. Mason

Keyword(s):

Feedback Loop ◽

Extracellular Volume ◽

Extracellular Fluid ◽

Tubuloglomerular Feedback ◽

Response Curves ◽

Fluid Delivery ◽

Fluid Load ◽

Single Nephron ◽

Distal Delivery ◽

Distal Flow

A closed-feedback loop micropuncture method was used to examine tubuloglomerular feedback (TGF) and the regulation of distal fluid delivery in hydropenic rats (CON), moderately hemorrhaged rats (HEM), and rats given desoxycorticosterone (DOC) and 0.6% saline to drink. Distal delivery and TGF response curves were measured with four samples per nephron: a spontaneous early distal collection, two distal collections during moderate (7.5 nl/min) and saturating (30 nl/min) perturbations in nephron fluid load, and a proximal collection to measure single-nephron glomerular filtration rate (SNGFR) during TGF inhibition. Arterial pressure, predistal volume reabsorption, SNGFR, and early distal flow were significantly higher in DOC than in HEM; the CON group exhibited intermediate values. Except for a greater maximum TGF response in HEM, the normalized TGF responses were similar in all three groups, as was the regulation of distal fluid delivery. However, the TGF onset threshold and the TGF operating point, defined by the spontaneous rates of early distal flow and SNGFR, were reset such that distal fluid delivery and SNGFR were higher in DOC than in HEM, as was renal sodium excretion. The results show that the level around which TGF stabilizes distal fluid delivery is reset when extracellular fluid volume is altered.

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Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF activity

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.1.f113 ◽

1999 ◽

Vol 277 (1) ◽

pp. F113-F120 ◽

Cited By ~ 19

Author(s):

Atsuhiro Ichihara ◽

L. Gabriel Navar

Keyword(s):

Initial Response ◽

Renal Perfusion ◽

Tubuloglomerular Feedback ◽

Afferent Arterioles ◽

Series Of Experiments ◽

Oxide Synthase ◽

Increased Activity ◽

Arteriolar Diameter ◽

Distal Delivery

To assess the afferent arteriolar autoregulatory response during increased activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent arteriolar diameter responses to changes in renal perfusion pressure (RPP) were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1 ± 1.4 μm ( n = 9). The initial and sustained constrictor responses of afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 ± 1.4% and 13.3 ± 1.3%, respectively. Acetazolamide treatment, which enhances TGF responsiveness by increasing distal nephron volume delivery, significantly decreased basal afferent arteriolar diameter by 8.2 ± 0.5% and enhanced the initial response (25.5 ± 2.3%) to a 60-mmHg increase in RPP but did not alter the sustained response (14.3 ± 1.5%). In another series of experiments, nNOS inhibition with 10 μM S-methyl-l-thiocitrulline (l-SMTC) significantly decreased afferent arteriolar diameter from 20.3 ± 1.3 to 18.3 ± 1.1 μm ( n = 7) and enhanced both the initial (34.4 ± 3.5%) and sustained constrictor responses (27.6 ± 2.9%) to a 60-mmHg increase in RPP. Treatment with acetazolamide further enhanced both initial (56.4 ± 3.0%) and sustained responses (54.6 ± 2.7%). Interruption of distal delivery by transection of the loops of Henle prevented the enhanced responses to increases in RPP elicited with either acetazolamide orl-SMTC. These results indicate that nNOS contributes to the counteracting resetting process of biphasic afferent arteriolar constrictor responses to increases in RPP through a TGF-dependent mechanism.

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Normal physiology of the renal system

10.1093/med/9780199600830.003.0208 ◽

2016 ◽

Author(s):

Bruce Andrew Cooper

Keyword(s):

Critical Care ◽

Critical Illness ◽

Renal Dysfunction ◽

Critical Role ◽

Renal Physiology ◽

Electrolyte Balance ◽

Care Environment ◽

System P ◽

Urine Production ◽

The Impact

Patients with critical illness often have renal dysfunction, either primary or secondary, that can both complicate and prolong their medical management. Therefore, an understanding of normal renal physiology can help recognize the process or processes that caused the renal dysfunction, and determine the most appropriate corrective and supportive care. The kidney has many important roles other than just urine production. The impact of kidney disease is often predictable. The kidney plays a critical role in fluid and electrolyte balance via many specialized transmembrane pathways. The kidney is also involved in the production and modification of two key hormones and one enzyme. Understanding normal renal physiology can help determine clinical management.This chapter summarizes the important aspects of renal physiology relevant to those who work in a critical care environment.

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