Type B intercalated cells secrete HCO3- and absorb Cl- across the apical plasma membrane through the action of the Cl-/HCO3- exchanger, pendrin. Pendrin-mediated Cl-/HCO3- exchange reduces arterial pH and HCO3- concentration, thereby attenuating a metabolic alkalosis. Pendrin-mediated Cl- absorption also contributes to the vascular volume expansion observed in rodent models of NaCl-sensitive hypertension, such as following a high NaCl diet and aldosterone analogues (deoxycorticosterone pivalate, DOCP). We have observed that the hypertension expected with DOCP administration and a high NaCl diet is not observed in mice with genetic disruption of the gene encoding pendrin (Slc26a4). The absence of aldosterone-induced hypertension in Slc26a4 null mice occurs most likely not only from the absence of pendrin-mediated Cl- uptake but also from the reduced epithelial Na+ channel (ENaC) expression observed in the kidneys of these mutant mice. However, pendrin and ENaC are regulated through both aldosterone-dependent and -independent mechanisms. Our laboratory and others have shown that angiotensin II stimulates Na+ and Cl- absorption in the cortical collecting duct (CCD) when perfused in vitro through synergy between pendrin and ENaC. How angiotensin II stimulates pendrin and ENaC expression and function and how pendrin and ENaC interact to promote NaCl absorption is the subject of the present proposal.
The aims of this proposal are the following: 1) to determine the mechanism whereby angiotensin II stimulates pendrin-mediated Cl-/HCO3- exchange in vitro and to determine how ENaC and pendrin interact following angiotensin II to increase NaCl absorption, 2) to determine the mechanism of the long-term regulation of pendrin by angiotensin II in vivo and how pendrin modulates ENaC expression in vivo and 3) to determine the mechanism for the interdependency of pendrin and ENaC expression. To accomplish these objectives wild type and genetically modified mice, such as Slc26a4 (-/-), total and cell-specific AT1a (-/-), tissue-specific ENaC (-/-) and mouse models of Liddle's Syndrome, will be studied using quantitative real time PCR, light microscopic immunohistochemistry, immunogold cytochemistry and immunoblots. Transport will be studied in mouse renal tubules perfused in vitro and in cultured mouse principal cells. Whole animal studies will be employed further in balance studies and measurements of blood pressure and GFR.7. Project Narrative: Our laboratory has observed that a protein called pendrin mediates absorption of chloride by the kidney, which increases blood pressure. In addition, pendrin also regulates absorption of sodium by the kidney by changing the amount of a protein that transports sodium within the kidney (i.e. the epithelial sodium channel, ENaC). This proposal will explore how pendrin controls absorption of sodium and chloride by the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK052935-11S1
Application #
7988978
Study Section
Special Emphasis Panel (ZRG1-RUS-C (02))
Program Officer
Ketchum, Christian J
Project Start
2009-12-15
Project End
2010-11-30
Budget Start
2009-12-15
Budget End
2010-11-30
Support Year
11
Fiscal Year
2010
Total Cost
$103,100
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Pech, Vladimir; Thumova, Monika; Kim, Young Hee et al. (2012) ENaC inhibition stimulates Cl- secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism. Am J Physiol Renal Physiol 303:F45-55
Verlander, Jill W; Hong, Seongun; Pech, Vladimir et al. (2011) Angiotensin II acts through the angiotensin 1a receptor to upregulate pendrin. Am J Physiol Renal Physiol 301:F1314-25
Wall, Susan M; Pech, Vladimir (2010) Pendrin and sodium channels: relevance to hypertension. J Nephrol 23 Suppl 16:S118-23
Leviel, Françoise; Hübner, Christian A; Houillier, Pascal et al. (2010) The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. J Clin Invest 120:1627-35
Pech, Vladimir; Pham, Truyen D; Hong, Seongun et al. (2010) Pendrin modulates ENaC function by changing luminal HCO3-. J Am Soc Nephrol 21:1928-41
Pech, Vladimir; Kim, Young Hee; Weinstein, Alan M et al. (2007) Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism. Am J Physiol Renal Physiol 292:F914-20
Verlander, Jill W; Kim, Young Hee; Shin, Wonkyong et al. (2006) Dietary Cl(-) restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells. Am J Physiol Renal Physiol 291:F833-9
Jabba, Sairam V; Oelke, Alisha; Singh, Ruchira et al. (2006) Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model. BMC Med 4:37
Wall, Susan M (2006) The renal physiology of pendrin (SLC26A4) and its role in hypertension. Novartis Found Symp 273:231-9; discussion 239-43, 261-4
Kim, Young-Hee; Verlander, Jill W; Matthews, Sharon W et al. (2005) Intercalated cell H+/OH- transporter expression is reduced in Slc26a4 null mice. Am J Physiol Renal Physiol 289:F1262-72

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