scholarly journals Renal Autoregulation in Health and Disease

2015 ◽  
Vol 95 (2) ◽  
pp. 405-511 ◽  
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.

The step response: a method to characterize mechanisms of renal blood flow autoregulation

2003 ◽  
Vol 285 (4) ◽  
pp. F758-F764 ◽  
Author(s):  
T. Wronski ◽  
E. Seeliger ◽  
P. B. Persson ◽  
C. Forner ◽  
C. Fichtner ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Perfusion ◽  
Oscillation Period ◽  
Tubuloglomerular Feedback ◽  
Step Response ◽  
Myogenic Response ◽  
Renal Vasculature ◽  
The Individual ◽  
Reported Data

Response of renal vasculature to changes in renal perfusion pressure (RPP) involves mechanisms with different frequency characteristics. Autoregulation of renal blood flow (RBF) is mediated by the rapid myogenic response, by the slower tubuloglomerular feedback (TGF) mechanism, and, possibly, by an even slower third mechanism. To evaluate the individual contribution of these mechanisms to RBF autoregulation, we analyzed the response of RBF to a step increase in RPP. In anesthetized rats, the suprarenal aorta was occluded for 30 s, and then the occlusion was released to induce a step increase in RPP. Three dampened oscillations were observed; their oscillation periods ranged from 9.5 to 13 s, from 34.2 to 38.6 s, and from 100.5 to 132.2 s, respectively. The two faster oscillations correspond with previously reported data on the myogenic mechanism and the TGF. In accordance, after furosemide, the amplitude of the intermediate oscillation was significantly reduced. Inhibition of nitric oxide synthesis by Nω-nitro-l-arginine methyl ester significantly increased the amplitude of the 10-s oscillation. It is concluded that the parameters of the dampened oscillations induced by the step increase in RPP reflect properties of autoregulatory mechanisms. The oscillation period characterizes the individual mechanism, the dampening is a measure for the stability of the regulation, and the square of the amplitudes characterizes the power of the respective mechanism. In addition to the myogenic response and the TGF, a third rather slow mechanism of RBF autoregulation exists.

Calciotropic and Magnesiotropic TRP Channels

Physiology ◽  
2008 ◽  
Vol 23 (1) ◽  
pp. 32-40 ◽  
Author(s):  
Joost G. J. Hoenderop ◽  
René J. M. Bindels
Keyword(s):  
Divalent Cation ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Significant Progress ◽  
Functional Aspects ◽  
Health And Disease ◽  
Transient Receptor

Significant progress has been made into our understanding of the molecular mechanisms responsible for Ca2+ and Mg2+ homeostasis. Members of the transient receptor potential channel (TRP) superfamily proved essential to the maintenance of divalent cation levels by regulating their absorption from renal and intestinal lumina. This review highlights the molecular and functional aspects of these new calciotropic and magnesiotropic TRPs in health and disease.

scholarly journals Aging Impairs Renal Autoregulation in Mice

Hypertension ◽  
2020 ◽  
Vol 75 (2) ◽  
pp. 405-412 ◽  
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.

TRPC3-Based Protein Signaling Complex as a Therapeutic Target of Myocardial Atrophy

2020 ◽  
Vol 14 (2) ◽  
pp. 123-131
Author(s):  
Kazuhiro Nishiyama ◽  
Tomohiro Tanaka ◽  
Akiyuki Nishimura ◽  
Motohiro Nishida
Keyword(s):  
Drug Treatment ◽  
Protein Interactions ◽  
Therapeutic Target ◽  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Interstitial Fibrosis ◽  
Receptor Potential ◽  
Cancer Drug ◽  
Myocardial Atrophy

Background: Transient receptor potential (TRP) channels, especially canonical TRP channel subfamily members 3 (TRPC3) and 6 (TRPC6), have attracted attention as a putative therapeutic target of heart | 1 failure. Moreover, TRPC3 and TRPC6 channels are physiologically important for maintaining cellular homeostasis. How TRPC3/C6 channels alter intracellular signaling from adaptation to maladaptation has been discussed for many years. We recently showed that formation of a protein signal complex between TRPC3 and NADPH oxidase (Nox) 2 caused by environmental stresses (e.g., hypoxia, nutritional deficiency, and anticancer drug treatment) promotes Nox2-dependent reactive oxygen species production and cardiac stiffness, including myocardial atrophy and interstitial fibrosis, in rodents. In fact, pharmacological prevention of the TRPC3-Nox2 protein complex can maintain cardiac flexibility in mice after anti-cancer drug treatment. Conclusion: In this mini-review, we discuss the relationship between TRPC3/C6 channels and cardiovascular disease, and propose a new therapeutic strategy by focusing on pathology-specific protein– protein interactions.

scholarly journals A gap junction inhibitor, carbenoxolone, induces spatiotemporal dispersion of renal cortical perfusion and impairs autoregulation

2016 ◽  
Vol 311 (3) ◽  
pp. H582-H591 ◽  
Author(s):  
Nicholas Mitrou ◽  
Branko Braam ◽  
William A. Cupples
Keyword(s):  
Gap Junctions ◽  
Spatial Variation ◽  
Gap Junction ◽  
Laser Speckle ◽  
Tubuloglomerular Feedback ◽  
Spatial And Temporal Variation ◽  
Contrast Imaging ◽  
Renal Vasculature ◽  
Renal Autoregulation ◽  
Gap Junction Inhibitor

Renal autoregulation dynamics originating from the myogenic response (MR) and tubuloglomerular feedback (TGF) can synchronize over large regions of the kidney surface, likely through gap junction-mediated electrotonic conduction and reflecting distributed operation of autoregulation. We tested the hypotheses that inhibition of gap junctions reduces spatial synchronization of autoregulation dynamics, abrogates spatial and temporal smoothing of renal perfusion, and impairs renal autoregulation. In male Long-Evans rats, we infused the gap junction inhibitor carbenoxolone (CBX) or the related glycyrrhizic acid (GZA) that does not block gap junctions into the renal artery and monitored renal blood flow (RBF) and surface perfusion by laser speckle contrast imaging. Neither CBX nor GZA altered RBF or mean surface perfusion. CBX preferentially increased spatial and temporal variation in the distribution of surface perfusion, increased spatial variation in the operating frequencies of the MR and TGF, and reduced phase coherence of TGF and increased its dispersion. CBX, but not GZA, impaired dynamic and steady-state autoregulation. Separately, infusion of the Rho kinase inhibitor Y-27632 paralyzed smooth muscle, grossly impaired dynamic autoregulation, and monotonically increased spatial variation of surface perfusion. These data suggest CBX inhibited gap junction communication, which in turn reduced the ability of TGF to synchronize among groups of nephrons. The results indicate that impaired autoregulation resulted from degraded synchronization, rather than the reverse. We show that network behavior in the renal vasculature is necessary for effective RBF autoregulation.

scholarly journals Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Gum Hwa Lee ◽  
Sang Seong Kim
Keyword(s):  
Neuropathic Pain ◽  
Sequence Analysis ◽  
Ion Channel ◽  
G Protein ◽  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Pain Treatment ◽  
Neuronal Damage ◽  
Rna Sequence

Chronic pain originating from neuronal damage remains an incurable symptom debilitating patients. Proposed molecular modalities in neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an important role in triggering surrounding immune cells. The multiple protein expressions complicate therapeutic development for neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for the incurable pain. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) facilitate the artificial manipulation of intracellular signaling through excitatory or inhibitory G protein subunits activated by biologically inert synthetic ligands. Expression of excitatory channelrhodopsins and inhibitory halorhodopsins on injured neurons or surrounding cells can attenuate neuropathic pain precisely controlled by light stimulation. To achieve the discrete treatment of injured neurons, we can exploit the transcriptome database obtained by RNA sequence analysis in specific neuropathies. This can recommend the suitable promoter information to target the injury sites circumventing intact neurons. Therefore, novel strategies benefiting from pharmacogenetics, optogenetics, and RNA sequencing might be promising for neuropathic pain treatment in future.

scholarly journals TRPM2 in the Brain: Role in Health and Disease

Cells ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 82 ◽  
Author(s):  
Giulia Sita ◽  
Patrizia Hrelia ◽  
Agnese Graziosi ◽  
Gloria Ravegnini ◽  
Fabiana Morroni
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Cell Functions ◽  
Neuroprotective Strategies ◽  
Health And Disease ◽  
Future Potential ◽  
Transient Receptor ◽  
Multiple Signaling ◽  
The Brain

Transient receptor potential (TRP) proteins have been implicated in several cell functions as non-selective cation channels, with about 30 different mammalian TRP channels having been recognized. Among them, TRP-melastatin 2 (TRPM2) is particularly involved in the response to oxidative stress and inflammation, while its activity depends on the presence of intracellular calcium (Ca2+). TRPM2 is involved in several physiological and pathological processes in the brain through the modulation of multiple signaling pathways. The aim of the present review is to provide a brief summary of the current insights of TRPM2 role in health and disease to focalize our attention on future potential neuroprotective strategies.

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

2006 ◽  
Vol 290 (5) ◽  
pp. R1153-R1167 ◽  
Author(s):  
Rodger Loutzenhiser ◽  
Karen Griffin ◽  
Geoffrey Williamson ◽  
Anil Bidani
Keyword(s):  
Critical Role ◽  
Systolic Pressure ◽  
Tubuloglomerular Feedback ◽  
Renal Physiology ◽  
Current View ◽  
Myogenic Response ◽  
Compensatory Mechanisms ◽  
Excretory Function ◽  
Renal Autoregulation ◽  
Distal Delivery

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.

Renal autoregulation: models combining tubuloglomerular feedback and myogenic response

1987 ◽  
Vol 252 (4) ◽  
pp. F768-F783 ◽  
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.

scholarly journals Modulation of Transient Receptor Potential (TRP) channels by tyrosine phosphorylation

2020 ◽  
Vol 3 (1) ◽  
pp. 77-87
Author(s):  
Alexandra Manolache ◽  
Teodora Stratulat ◽  
Alexandru Babeș
Keyword(s):  
Oxidative Stress ◽  
Nervous System ◽  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Diverse Range ◽  
Transient Receptor ◽  
Intracellular Signaling Molecules

Transient Receptor Potential (TRP) channels are a superfamily of polymodal, non-selective receptors, expressed in the nervous system and several other tissues, where they play many physiological or pathological roles. TRP channels are sensitive to a diverse range of stimuli, such as temperature, osmolarity, oxidative stress, external compounds and intracellular signaling molecules. The activity of TRP channels can be modulated by protein phosphorylation, including tyrosine phosphorylation. In this review, we present the studies carried out so far regarding the modulation of TRP channels by tyrosine phosphorylation.

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