Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na<sup>+</sup>/Ca<sup>2+</sup>exchanger knockout mice

Zhao, Di; Zhang, Jin; Blaustein, Mordecai P.; Navar, L. Gabriel

doi:10.1152/ajprenal.00065.2011

Cited by 9 publications

(9 citation statements)

References 39 publications

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“…Knockout of NCX1 in VSMCs reduced vasoconstriction elicited by PE, high KCl, PP, or L-type Ca 2ϩ channel currents in mouse mesenteric arteries and lowered BP (1655). Myogenic and ANG II responses of mesenteric arteries were blunted in mutant mice lacking the NCX1 in VSMCs (1655,1660) accompanied by attenuated Ca 2ϩ entry and myogenic responses (1010,1655).…”

Section: Sodium Channelsmentioning

confidence: 99%

Renal Autoregulation in Health and Disease

Carlström

Wilcox

Arendshorst

2015

Physiological Reviews

391

383

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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.

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Section: Sodium Channelsmentioning

confidence: 99%

Renal Autoregulation in Health and Disease

Carlström

Wilcox

Arendshorst

2015

Physiological Reviews

391

383

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“…11) (99; 120; 193; 590; 591). However, whether the Na + /Ca 2+ exchanger plays an important role in the regulation of proximal tubular sodium and fluid reabsorption in the kidney has not been studied in transgenic animals with global or cell-specific deletion or expression of the Na + /Ca 2+ exchangers (53; 573; 574). Generation of transgenic mice with deficiency or overexpression of the Na + /Ca 2+ exchangers, NCX1, NCX2 or NCX3, selectively in proximal tubules of the kidney may be necessary to further determine the role of these Na + /Ca 2+ exchangers in proximal tubules.…”

Section: Physiological Regulation Of Proximal Tubule Functionsmentioning

confidence: 99%

Proximal Nephron

Zhuo,

2013

Comprehensive Physiology

174

140

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The kidney plays a fundamental role in maintaining body salt and fluid balance and blood pressure homeostasis through the actions of its proximal and distal tubular segments of nephrons. However, proximal tubules are well recognized to exert a more prominent role than distal counterparts. Proximal tubules are responsible for reabsorbing approximately 65% of filtered load and most, if not all, of filtered amino acids, glucose, solutes, and low molecular weight proteins. Proximal tubules also play a key role in regulating acid-base balance by reabsorbing approximately 80% of filtered bicarbonate. The purpose of this review article is to provide a comprehensive overview of new insights and perspectives into current understanding of proximal tubules of nephrons, with an emphasis on the ultrastructure, molecular biology, cellular and integrative physiology, and the underlying signaling transduction mechanisms. The review is divided into three closely related sections. The first section focuses on the classification of nephrons and recent perspectives on the potential role of nephron numbers in human health and diseases. The second section reviews recent research on the structural and biochemical basis of proximal tubular function. The final section provides a comprehensive overview of new insights and perspectives in the physiological regulation of proximal tubular transport by vasoactive hormones. In the latter section, attention is particularly paid to new insights and perspectives learnt from recent cloning of transporters, development of transgenic animals with knockout or knockin of a particular gene of interest, and mapping of signaling pathways using microarrays and/or physiological proteomic approaches.

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“…Transient receptor potential canonical channels and the Na/Ca exchanger also contribute to Ang II mediated vasoconstriction (59), and P/Q-type calcium channels contribute to depolarization-induced vasoconstriction (60). The acute renal vascular constriction to Ang II was found to be attenuated in mice lacking Na+/Ca2+ exchanger in vascular smooth muscle (61). There is a myriad of intracellular signaling pathways that are activated by AT1 receptors including G-protein-derived second messengers, protein kinases, small G-proteins, growth factor receptors, NADPH oxidases and Rho and its effector Rho-kinase (62–64).…”

Section: Intracellular Mechanismsmentioning

confidence: 99%

Intrarenal renin–angiotensin system in regulation of glomerular function

Navar

2014

Current Opinion in Nephrology and Hypertension

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Purpose of Review The purpose of this review is to provide an update on the current knowledge regarding the role of the intrarenal renin-angiotensin system (RAS) in the regulation of glomerular function including glomerular dynamics and filtration rate, glomerular permeability and structural alterations during chronic increases in intrarenal Ang II. Recent Findings Recent studies have continued to delineate the complex interactions among the various RAS components that participate in regulating glomerular function. While angiotensin (Ang) II acting on AT1 receptors remains as the predominant influence on glomerular dynamics some of these effects are indirectly mediated by Ang II modulating the sensitivity of the macula densa tubuloglomerular feedback mechanism as well as the more recently described feedback mechanism from the connecting tubule. Interestingly, the actions of Ang II on these systems cause opposite effects on glomerular function demonstrating the complexities associated with the influences of Ang II on glomerular function. When chronically elevated, Ang II also stimulates and/or interacts with other factors including reactive oxygen species, cytokines and growth factors and other hormones or paracrine agents to elicit structural alterations. Summary Recent studies have provided further evidence for the presence of many components of the RAS in glomerular structures supporting the importance of locally produced angiotensin peptides to regulate glomerular hemodynamics, filtration rate, macromolecular permeability and contribute to fibrosis and glomerular injury when inappropriately augmented.

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Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na⁺/Ca²⁺exchanger knockout mice

Cited by 9 publications

References 39 publications

Renal Autoregulation in Health and Disease

Renal Autoregulation in Health and Disease

Proximal Nephron

Intrarenal renin–angiotensin system in regulation of glomerular function

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Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na+/Ca2+exchanger knockout mice

Cited by 9 publications

References 39 publications

Renal Autoregulation in Health and Disease

Renal Autoregulation in Health and Disease

Proximal Nephron

Intrarenal renin–angiotensin system in regulation of glomerular function

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Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na⁺/Ca²⁺exchanger knockout mice