Activation of the renal renin-angiotensin system in diabetes--new concepts

Peti‐Peterdi, Janos; Kang, Jung Julie; Toma, Ildikó

doi:10.1093/ndt/gfn377

Cited by 81 publications

(76 citation statements)

References 31 publications

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“…Although the JGA is recognized as the primary source of active renin and the gatekeeper of early RAS activation, the elevating angiotensin II levels eventually suppress JGA renin but stimulate its synthesis mainly in the form of prorenin in the collecting duct system. 12 In fact, plasma prorenin levels are high in diabetes, 32 and the collecting duct was suggested as the main source. 33 Prorenin activation via binding to the recently identified prorenin receptor 34 may explain the persistent intrarenal RAS activity in diabetes despite the suppression of JGA and plasma active renin.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release

Vargas¹,

Toma²,

Kang³

et al. 2009

Journal of the American Society of Nephrology

133

135

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Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) are salt sensors and generate paracrine signals that control renal blood flow, glomerular filtration, and release of the prohypertensive hormone renin. We hypothesized that the recently identified succinate receptor GPR91 is present in MD cells and regulates renin release. Using immunohistochemistry, we identified GPR91 in the apical plasma membrane of MD cells. Treatment of MD cells with succinate activated mitogen-activated protein kinases (MAPKs; p38 and extracellular signal-regulated kinases 1/2) and cyclooxygenase 2 (COX-2) and induced the synthesis and release of prostaglandin E 2 , a potent vasodilator and classic paracrine mediator of renin release. Using microperfused JGA and real-time confocal fluorescence imaging of quinacrinelabeled renin granules, we detected significant renin release in response to tubular succinate (EC 50 350 M). Genetic deletion of GPR91 (GPR91 Ϫ/Ϫ mice) or pharmacologic inhibition of MAPK or COX-2 blocked succinate-induced renin release. Streptozotocin-induced diabetes caused GPR91-dependent upregulation of renal cortical phospho-p38, extracellular signal-regulated kinases 1/2, COX-2, and renin content. Salt depletion for 1 wk increased plasma renin activity seven-fold in wild-type mice but only 3.4-fold in GPR91 Ϫ/Ϫ mice. In summary, MD cells can sense alterations in local tissue metabolism via accumulation of tubular succinate and GPR91 signaling, which involves the activation of MAPKs, COX-2, and the release of prostaglandin E 2 . This mechanism may be integral in the regulation of renin release and activation of the renin-angiotensin system in health and disease.

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Section: Discussionmentioning

confidence: 99%

Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release

Vargas¹,

Toma²,

Kang³

et al. 2009

Journal of the American Society of Nephrology

133

135

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“…In particular, the expression and regulation of (pro)renin in the connecting tubule and collecting duct have attracted attention over the last few years (729). Renin expression in this localization may be important under conditions of high ANG II states like diabetes (417,688) and renovascular hypertension (702).…”

Section: Sites Of Renin Expressionmentioning

confidence: 99%

Physiology of Kidney Renin

Castrop

Höcherl

Kurtz

et al. 2010

Physiological Reviews

232

277

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The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).

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“…As such, SUCNR1 may allow the body to escape from the angiotensin II-negative feedback loop and maintain high levels of (pro)renin, thereby contributing to sustained hypertension. [25][26][27] Nowadays, it is well established that the production and release of renin is no longer restricted to the JGA, and individual components of the renin-angiotensin system have been detected throughout the nephron. 28 The function of this paracrine tubular renin-angiotensin system is slowly emerging.…”

Section: Regulation Of Bp and The Renin-angiotensin System In The Diamentioning

confidence: 99%