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/jci200523378

Cited by 188 publications

(206 citation statements)

References 36 publications

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“…We used a kidney crosstransplantation strategy to separate the actions of AT 1 receptor pools in the kidney from those in systemic tissues, as we have described previously (21). Kidney transplantation was carried out between genetically matched F 1 (C57BL͞6 ϫ 129) wild-type mice and F 1 (C57BL͞6 ϫ 129) mice homozygous for a targeted disruption of the Agtr1a gene locus encoding the AT 1A receptor (14).…”

Section: Resultsmentioning

confidence: 99%

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Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Crowley

Gurley

Herrera

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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624

542

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Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT 1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT 1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT 1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT 1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney. transgenic mice ͉ kidney transplantation ͉ blood pressure H igh blood pressure (BP) is a highly prevalent disorder, and its complications (including heart disease, stroke, and kidney disease) are a major public health problem (1). Despite decades of scrutiny, the precise pathogenesis of essential hypertension has been difficult to delineate. Guyton and his associates suggested that defective handling of sodium by the kidney and consequent dysregulation of body fluid volumes is a requisite, final common pathway in hypertension pathogenesis (2). The powerful capacity of this pathway to modulate blood pressure is illustrated by the elegant studies of Lifton and associates showing that virtually all of the Mendelian disorders with major impact on blood pressure homeostasis are caused by genetic variants affecting salt and water reabsorption by the distal nephron (3). On the other hand, several recent studies have suggested that primary vascular defects may cause hypertension by impacting peripheral resistance without direct involvement of renal excretory functions (4-7).Among the various regulatory systems that impact blood pressure, the RAS has a key role. Inappropriate activation of the RAS, as in renal artery stenosis, leads to profound hypertension and cardiovascular morbidity (8). Moreover, in patients with essential hypertension who typically lack overt signs of RAS activation, ACE inhibitors and angiotensin receptor blockers (ARBs) effectively reduce blood pressure and ameliorate cardiovascular complications (9-11), suggesting that dysregulation of the RAS contributes to their elevated blood pressure.

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Section: Resultsmentioning

confidence: 99%

“…One week after placement of these units, when the animals had regained normal diurnal variation of blood pressure, blood pressure measurement was initiated. (21) showing that renal and systemic AT 1 receptors make equivalent contributions to the level of blood pressure in the basal state.…”

Section: Resultsmentioning

confidence: 99%

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Crowley

Gurley

Herrera

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

624

542

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“…5,6 Our recent experiments have suggested that actions of the renin-angiotensin system (RAS) are tissue dependent in the setting of various CKDs. [7][8][9] Despite the wide use of RAS inhibitors, including type 1 angiotensin receptor blockers (ARBs), little evidence is available to direct the use of these medicines when a patient is at risk of developing AKI. During persistent hypertension, we found that inactivation of type 1 angiotensin II (AT 1 ) receptors on T lymphocytes led to exaggerated generation of TNF through the induction of the Th1 transcription factor T-bet.…”

mentioning

confidence: 99%

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

Zhang¹,

Rudemiller²,

Patel³

et al. 2016

JASN

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Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT 1 ) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-a is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-a is suppressed or enhanced by AT 1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT 1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-a levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT 1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-a production induced by cisplatin. Finally, disrupting TNF-a production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-a levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT 1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.

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“…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.Renal autoregulation maintains renal blood flow and GFR, independent of perfusion pressure between 80 and 180 mmHg, and protects the kidney from hypertensive injury. 5,8 This is afforded by myogenic and macula densa (MD) tubuloglomerular feedback responses.…”

mentioning

confidence: 99%

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confidence: 99%

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

José

Welch

2016

JASN

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Hypertension is present in about 40% of the world's population, and it is responsible for 12.8% of total deaths. 1 However, these statistics do not include normotensive individuals who are salt (NaCl)-sensitive. 2 Salt sensitivity, independent of BP, is a risk factor for not only cardiovascular morbidity and mortality but also other diseases, including metabolic syndrome. [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.Renal autoregulation maintains renal blood flow and GFR, independent of perfusion pressure between 80 and 180 mmHg, and protects the kidney from hypertensive injury. 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. 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. 10 Lu et al. 11 have previously reported that splice variants of nNOS in MD cells may be important in the regulation of tubuloglomerular feedback during salt loading.In this report, Lu et al. 12 extend the aforementioned study by testing the hypothesis that nitric oxide synthase 1b (NOS1b) may be the salt-sensitive isoform of NOS1 in the MD that modulates tubuloglomerular feedback response, promotes sodium excretion, and protects against the development of salt-sensitive hypertension. To test this hypothesis, Lu et al. 12 deleted all of the NOS1 splice variants specifically from the MD of C57Bl/6 mice. Compared with control wild-type mice, mice with MD-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had enhanced tubuloglomerular feedback response after acute volume expansion, and their BPs were increased by a high-salt diet. Relative to wild-type mice, MD-NOS1KO mice on a high-salt diet also had greater BP responses to chronic infusion of angiotensin II. Because MD nitric oxide production was similar in the isolated perfused juxtaglomerular apparatus of wild-type and NOS1a-knockout mice, these studies suggest that the phenotype that results from MD-NOS1KO is caused by NOS1b. Although a more direct evaluation of the specific NOS1 isoform in the regulation of tubuloglomerular feedback would have been MDspecific deletion of NOS1b, these elegant experiments support the conclusion that NOS1b is the salt-sensitive isoform of NOS1 expressed in the MD that regulates the tubuloglomerular feedback response and protects against the development of saltsensitive h...

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

Cited by 188 publications

References 36 publications

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

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

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