Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system

Crowley, Steven D.; Gurley, Susan B.; Oliverio, Michael I.; Pazmino, A. Kathy; Griffiths, Robert; Flannery, Patrick J.; Spurney, Robert F.; Kim, Hyung Suk; Smithies, Oliver; Le, Thu H.; Coffman, Thomas M.

doi:10.1172/jci23378

Cited by 275 publications

(123 citation statements)

References 46 publications

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“…Our previous studies using kidney cross-transplantation showed that AT 1A receptors within the kidney are crucial for regulation of blood pressure 4 and for the development of hypertension 5 . Within the kidney, AT 1 receptors are broadly expressed by epithelial cells across the nephron where they have been shown to have potent influence on sodium reabsorption 3 .…”

Section: Discussionmentioning

confidence: 99%

“…The major effector peptide of the RAS, angiotensin II (Ang II), is generated by sequential cleavage of the substrate angiotensinogen and acts via the angiotensin type 1 (AT 1 ) receptor to increase blood pressure 2, 3 . Studies from our laboratory using kidney cross-transplantation have demonstrated the critical role of AT 1 receptors inside the kidney to control blood pressure 4 and to promote hypertension 5 . In the kidney, AT 1 receptors are ubiquitously expressed in glomeruli, vascular and renal epithelia 6 .…”

Section: Introductionmentioning

confidence: 99%

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Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension

et al. 2016

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The main actions of the renin-angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT1Rs). The major murine AT1R isoform, AT1AR, is expressed throughout the nephron, including the collecting duct in both principal and intercalated cells. Principal cells play the major role in sodium and water reabsorption. Although aldosterone is considered to be the dominant regulator of sodium reabsorption by principal cells, recent studies suggest a role for direct actions of AT1R. In order to specifically examine the contributions of AT1AR in principal cells to BP regulation and the development of hypertension in vivo, we generated inbred 129/SvEv mice with deletion of AT1AR from principal cells (PCKO). At baseline, we found that BPs measured by radiotelemetry were similar between PCKOs and controls. During one-week of low salt diet (<0.02% NaCl), BPs fell significantly (P<0.05) and to a similar extent in both groups. On a high salt (6% NaCl) diet, BP increased but was not different between groups. During the initial phase of Ang II-dependent hypertension, there was a modest but significant attenuation of hypertension in PCKOs (163±6 mmHg) compared to controls (178±2 mmHg, P<0.05) that was associated with enhanced natriuresis and decreased αENaC activation in the medulla of PCKOs. However, from day 9 onward, BPs were indistinguishable between groups. While effects of AT1AR on baseline BP and adaptation to changes in dietary salt are negligible, our studies suggest that direct actions of AT1AR contribute to the initiation of hypertension and ENaC activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension

et al. 2016

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“…Angiotensin II (ANG II) is the main active peptide of the renin-angiotensin system and plays a prominent role in maintaining blood pressure and body fluid and electrolyte balance homeostasis [2]. Dopamine (DA) and ANG II exhibit opposed physiological effects.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II Regulation of Renal Dopamine Uptake and Na<sup>+</sup>,K<sup>+</sup>-ATPase Activity

et al. 2009

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Background/Aims: Angiotensin II (ANG II) decreases dopamine (DA) uptake in renal cortex activating AT₁ receptors. We investigated the signaling pathways that mediate this action and the incidence of DA-ANG II interaction on renal Na⁺,K⁺-ATPase activity. Methods: ANG II effects on [³H]-DA uptake and Na⁺,K⁺-ATPase were measured in samples from the outer renal cortex of Sprague-Dawley rats. Results: Inhibition of the phospholipase C (PLC) pathway blunted ANG II inhibitory effects on [³H]-DA uptake, since U-73122, 2-APB, TMB-8, chelerythrine and KN-93 (PLC, IP₃-dependent Ca²⁺ release channels, IP₃ receptors, protein kinase C and CaM kinase II inhibitors, respectively) each one blocked ANG II effects. Inhibition of adenylate cyclase pathway did not modify ANG II inhibitory effects on DA uptake. ANG II effects on [³H]-DA uptake were able to modify Na⁺,K⁺-ATPase activity in carbidopa-treated rats. Exogenous DA decreased while ANG II increased the enzyme activity. Neither the addition of DA together with ANG II, nor the extraneuronal DA uptake blocker hydrocortisone altered ANG II stimulatory effects on Na⁺,K⁺-ATPase activity, but hydrocortisone blocked the inhibitory effects of exogenous DA. Conclusion: Stimulation of renal AT₁ receptors by ANG II signals through the PLC pathway to inhibit extraneuronal DA uptake. DA and ANG II act through a common pathway involving reversible renal tubular Na⁺,K⁺-ATPase deactivation and activation, respectively. In addition, ANG II by itself is able to stimulate renal Na⁺,K⁺-ATPase activity.

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“…4 Among them, the kidneys have been demonstrated to play a vital role in the development of hypertension in both humans and experimental animal models. 5,6 Kidneys transplanted from hypertensive donors increase BP in normotensive recipients, whereas kidneys transplanted from normotensive donors lower BP in hypertensive recipients both in clinical 7–10 and experimental renal transplantation studies. 11–14 …”

Section: Introductionmentioning

confidence: 99%

Role of Kidneys in Sex Differences in Angiotensin II–Induced Hypertension

Wang

et al. 2017

Hypertension

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The significance of kidneys in regulation of sodium and water balance and hemodynamics has been demonstrated both in patients and animal models. In the present study, we tested our hypothesis that kidneys play an essential role in control of sex differences in Ang II-dependent hypertension. Kidney transplantations (KTXs) were performed between male and female C57BL/6 mice (F, female; M, male; donor→recipient: F→F; M→M; F→M; and M→F). Radio-telemetry transmitters were implanted for measurement of mean arterial pressure (MAP) during the infusion of Ang II (600ng/kg/min). Gene expressions and inflammatory responses in the transplanted grafts were assessed. We found that same-sex-KTX mice still exhibited sex differences in Ang II-dependent hypertension (31.3±0.8 mmHg in M→M vs. 12.2±0.6 mmHg in F→F), which were reduced between M and F when they received kidneys of the opposite sex (32.9±1 mmHg in M→F vs. 22.3±0.7 mmHg in F→M). The sex differences in gene expressions, including AT1, AT1/AT2, ET1, ETA, NHE3, αENaC and γENaC, were unaltered in same-sex KTX and much lessened in cross-sex KTXs. In addition, the cross-sex KTXs exhibited more robust inflammatory responses reflected by higher expression of IL-6, TNFα, and KC than same-sex KTX. Our results indicate that kidneys play an essential role in sex differences of Ang II-dependent hypertension. KTX of male kidneys to females augmented the BP response while KTX of female kidneys to males attenuated the BP response. The host’s extra-renal systems modulate expressions of many genes and inflammatory response, which may also contribute to the sex differences in blood pressure regulation.

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Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system

Cited by 275 publications

References 46 publications

Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension

Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension

Angiotensin II Regulation of Renal Dopamine Uptake and Na<sup>+</sup>,K<sup>+</sup>-ATPase Activity

Role of Kidneys in Sex Differences in Angiotensin II–Induced Hypertension

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