Epithelial Na channels are expressed in the distal parts of the mammalian nephron, and are known to be regulated by the renin-angiotensin-aldosterone axis. The role of these channels and their regulation by mineralocorticoids in the daily regulation of sodium excretion by the kidneys will be explored. Preliminary data indicate that when rats are given a low sodium diet, they can adjust their renal Na excretion within 15 hours and that increased reabsorption through Na channels can account for a large fraction of the reduced excretion rates. We will assess the role of the channels with different degrees of Na depletion, measuring both channel activity and overall urinary Na excretion. Channel activity will be measured as amiloride-sensitive whole-cell currents in the renal cortical collecting tubule as well as the medullary collecting duct and the connecting tubule to quantitate its contribution to renal Na handling. We will further test for the importance of Na channels by measuring Na excretion in rats treated with the channel blocker amiloride. Upregulation of other transport pathways will also be examined using thiazides to block NaCI cotransport and angiotensin receptor antagonists to prevent upregulation of Na/H exchange. We will also assess the roles of two putative signaling pathways for aldosterone secretion under these conditions, increased renin activity and elevated plasma K. We will explore the mechanisms of pathological upregulation seen in the Liddle's Syndrome form of human hypertension. This will be done using mice in which the channel subunit B-ENaC has been truncated to mimic the human mutation. Here we will test the idea that the mutation decreases the rate of downregulation of previously activated channels. Finally we will study the effects of insulin on the channels. We will examine the hypothesis that this hormone increases the open probability of channels inserted or activated by aldosterone. The results should help to understand the role of channel-mediated Na reabsorption under conditions of physiological (dietary) stress and hypertension.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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Ketchum, Christian J
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Weill Medical College of Cornell University
Schools of Medicine
New York
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Gleason, Catherine E; Frindt, Gustavo; Cheng, Chih-Jen et al. (2015) mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. J Clin Invest 125:117-28
Carattino, Marcelo D; Mueller, Gunhild M; Palmer, Lawrence G et al. (2014) Prostasin interacts with the epithelial Na+ channel and facilitates cleavage of the ?-subunit by a second protease. Am J Physiol Renal Physiol 307:F1080-7
Patel, Ankit B; Frindt, Gustavo; Palmer, Lawrence G (2013) Feedback inhibition of ENaC during acute sodium loading in vivo. Am J Physiol Renal Physiol 304:F222-32
Frindt, Gustavo; Palmer, Lawrence G (2012) Regulation of epithelial Na+ channels by adrenal steroids: mineralocorticoid and glucocorticoid effects. Am J Physiol Renal Physiol 302:F20-6
Patel, Ankit B; Chao, Julie; Palmer, Lawrence G (2012) Tissue kallikrein activation of the epithelial Na channel. Am J Physiol Renal Physiol 303:F540-50
Frindt, Gustavo; Palmer, Lawrence G (2012) Effects of insulin on Na and K transporters in the rat CCD. Am J Physiol Renal Physiol 302:F1227-33
Frindt, Gustavo; Houde, VĂ©ronique; Palmer, Lawrence G (2011) Conservation of Na+ vs. K+ by the rat cortical collecting duct. Am J Physiol Renal Physiol 301:F14-20
Frindt, Gustavo; Palmer, Lawrence G (2010) Effects of dietary K on cell-surface expression of renal ion channels and transporters. Am J Physiol Renal Physiol 299:F890-7
Schreiner, Ryan; Frindt, Gustavo; Diaz, Fernando et al. (2010) The absence of a clathrin adapter confers unique polarity essential to proximal tubule function. Kidney Int 78:382-8
Frindt, Gustavo; Palmer, Lawrence G (2009) Surface expression of sodium channels and transporters in rat kidney: effects of dietary sodium. Am J Physiol Renal Physiol 297:F1249-55

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