An unexpected role for angiotensin II in the link between dietary salt and proximal reabsorption

Thomson, Scott C.; Deng, Aihua; Wead, Lucinda M.; Richter, Kerstin; Blantz, Roland C.; Vallon, Volker

doi:10.1172/jci26092

Cited by 67 publications

(60 citation statements)

References 34 publications

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“…The PT is a well-characterized target of ANG II action (6,31) and NHE3 transport activity has been reported to be increased by ANG II treatment in cultured cells (9). Previous in vivo studies of the effects of ANG II infusion on PT transporters (33,38) are complicated by the fact that the ANG II infusion protocols usually raise BP (7), which is known to depress PT Na ϩ reabsorption (44), making it difficult to dissect out the effects of ANG II alone.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli

Riquier‐Brison

Leong

Pihakaski-Maunsbach

et al. 2010

American Journal of Physiology-Renal Physiology

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(ANG II) stimulates proximal tubule (PT) sodium and water reabsorption. We showed that treating rats acutely with the angiotensin-converting enzyme inhibitor captopril decreases PT salt and water reabsorption and provokes rapid redistribution of the Na ϩ /H ϩ exchanger isoform 3 (NHE3), Na ϩ /Pi cotransporter 2 (NaPi2), and associated proteins out of the microvilli. The aim of the present study was to determine whether acute ANG II infusion increases the abundance of PT NHE3, NaPi2, and associated proteins in the microvilli available for reabsorbing NaCl. Male Sprague-Dawley rats were infused with a dose of captopril (12 g/min for 20 min) that increased PT flow rate ϳ20% with no change in blood pressure (BP) or glomerular filtration rate (GFR). When ANG II (20 ng⅐kg Ϫ1 ⅐min Ϫ1 for 20 min) was added to the captopril infusate, PT volume flow rate returned to baseline without changing BP or GFR. After captopril, NHE3 was localized to the base of the microvilli and NaPi2 to subapical cytoplasmic vesicles; after 20 min ANG II, both NHE3 and NaPi2 redistributed into the microvilli, assayed by confocal microscopy and density gradient fractionation. Additional PT proteins that redistributed into low-density microvilli-enriched membranes in response to ANG II included myosin VI, DPPIV, NHERF-1, ezrin, megalin, vacuolar H ϩ -ATPase, aminopeptidase N, and clathrin. In summary, in response to 20 min ANG II in the absence of a change in BP or GFR, multiple proteins traffic into the PT brush-border microvilli where they likely contribute to the rapid increase in PT salt and water reabsorption. hypertension; captopril ANGIOTENSIN II (ANG II), a potent vasoconstrictor and sodiumretaining hormone, is crucial for the regulation of sodium transport in the kidneys and therefore for blood pressure (BP) homeostasis. Strong evidence highlights the contribution of high ANG II levels to the development of cardiovascular and renal diseases (23, 37). Consequently, drugs affecting the renin-angiotensin system (RAS), and in particular angiotensinconverting enzyme inhibitors (ACEI) and angiotensin receptor blockers, are commonly used for the treatment of high BP.The angiotensin type I receptor (AT1R) is responsible for the Na ϩ -retaining effects of ANG II. The renal proximal tubule (PT) expresses AT1R on both the apical and basolateral membranes and ANG II is delivered via the general circulation or filtered at the glomerulus. In addition, the PT cells synthesize all the components necessary to produce and secrete ANG II into its lumen: angiotensinogen, renin, and ACE (14, 29). ANG II has been shown to increase PT sodium and water reabsorption, and ACE inhibitors and AT1R blockers decrease PT sodium and water reabsorption (10, 13). The sodium hydrogen exchanger isoform 3 (NHE3) is the main transporter mediating sodium reabsorption in the PT (20) and cultured kidney cell studies indicate that ANG II can rapidly increase NHE3 abundance and activity in the plasma membrane (9).We recently investigated the molecular mechanisms responsible for th...

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Section: Discussionmentioning

confidence: 99%

Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli

Riquier‐Brison

Leong

Pihakaski-Maunsbach

et al. 2010

American Journal of Physiology-Renal Physiology

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“…In normal subjects, GFR is either insensitive to dietary NaCl or changes in the same direction as NaCl intake (142,150). In 1995, we reported that a low-salt diet (for 7-8 days after 6 wk of diabetes) increased renal blood flow, GFR, and kidney weight in male STZ-diabetic rats (160).…”

Section: Salt Paradox In the Diabetic Kidney-link To Proximal Tubularmentioning

confidence: 99%

The proximal tubule in the pathophysiology of the diabetic kidney

Vallon

2011

American Journal of Physiology-Regulatory, Integrative and Comp

319

306

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Diabetic nephropathy is a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved in the early changes of the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review focuses on the proximal tubule in the early diabetic kidney, particularly on its exposure and response to high glucose levels, albuminuria, and other factors in the diabetic glomerular filtrate, the hyperreabsorption of glucose, the unique molecular signature of the tubular growth phenotype, including aspects of senescence, and the resulting cellular and functional consequences. The latter includes the local release of proinflammatory chemokines and changes in proximal tubular salt and fluid reabsorption, which form the basis for the strong tubular control of glomerular filtration in the early diabetic kidney, including glomerular hyperfiltration and odd responses like the salt paradox. Importantly, these early proximal tubular changes can set the stage for oxidative stress, inflammation, hypoxia, and tubulointerstitial fibrosis, and thereby for the progression of diabetic renal disease.

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“…This shows a marked difference from the effect of ANG II on afferent arterioles in high renin hypertension models (22,24) and during ANG II blockade in vivo (61). ANG II increases tubular sodium reabsorption (47), although reabsorption may be decreased by ANG II in the proximal nephron (37,64). Intrarenal ANG II is important for renal function in hypertension (48) and for the proximal tubular natriuretic effect of ANG II through stimulation of AT2 receptors (29).…”

Section: Renin-angiotensinmentioning

confidence: 99%