The collecting duct plays a major role in the excretion of total ammonia (NH3 and NH4 plus), the major regulatable component of urinary net acid excretion. Ammonium (NH4plus) secretion by the collecting duct is attributed to active proton secretion in parallel with the passive diffusion of NH3. However, our laboratory has demonstrated direct NH4plus transport in the terminal inner medullary collecting duct (tlMCD). We have shown that NH4plus and Kplus compete for a common binding site on the Naplus minus- ATPase and that inhibition of the Naplus pump decrease transepithelial net acid secretion through blockade o Na plus minus pump mediated NH 4 plus transport. Uptake of NH4 plus across the basolateral membrane of the tlMCD by the Naplus minusKplus - ATPase, provides a source of Hplus for luminal acidification and the titration of other luminal buffers. Unlike the m ore proximal collecting duct segments, in the tlMCD interstitial and luminal NH3 and NH4plus concentrations have been measured. Thus, transporter mediated NH4plus flux can be placed in context with known NH3 and NH4 plus gradients to determine the physiological role for Na plus pump-mediated NH 4 plus transport. However, it is not known if changes in Na plus pump activity in vivo regulate transepithelial net acid secretion. If net acid secretion across the apical membrane is increased following in vivo conditioning, it is expected that across the basolateral membrane net Hplus uptake or OH/HCO3 exit would increase in parallel. This project will determine if Na plus pump number and Na plus pump-mediated ion transport are regulated by aldosterone administration in vivo. We will then test if Na plus pump activity increases, in parallel, with both total and ouabain-sensitive NH4 plus uptake and transepithelial net acid secretion. Hence, we will establish if changes in NH4 plus uptake in vivo regulate net acid secretion.
Aims of this proposal are to determine the following in the rat tlMCD: 1) If mineralocorticoid increases Na plus, K plus -ATPase-mediated ion transport and Na plus pump number. 2) If mineralocorticoid increases NH 4 plus uptake across the basolateral membrane. 3) If mineralocorticoid increases total and ouabain-sensitive net acid secretion and 4) If mineralocorticoid stimulates other basolateral H plus or OH/HCO3 transport pathways, providing a source of protons for apical secretion.
The aims will be addressed using isotopes and immunoblots of tlMCD cells in suspension. Observations will be extended using tlMCD tubules perfused in vitro.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG4-GMB (04))
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Scherbenske, M James
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University of Texas Health Science Center Houston
Internal Medicine/Medicine
Schools of Medicine
United States
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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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