Abstract

Keeping serum K+ within narrowly defined limits is critical for the maintenance of life. K+ homeostasis is an essential need of the body, but the means by which K^+ is conserved are poorly understood. K+-sparing is an important homeostatic component in response to volume depletion as may occur in such conditions as diarrhea, diuretic use, and congestive heart failure. The kidney adapts to volume depletion by reabsorbing more NaCI but the means by which K+ is conserved when NaCI is reabsorbed is not understood. The overall objective of this project is to elucidate the renal K+ conserving mechanisms involved in the adaptation to hypovolemia. I propose that K reabsorption occurs in volume depletion via a mechanism involving H+-K+-ATPase proteins present in the intercalated cells of the cortical collecting duct and these proteins are responsible for preserving K+-balance under conditions of volume depletion. Further, I propose that the apical Cl-/HCO-3 exchanger in the base secreting intercalated cell subtype, in cortical collecting duct, is the mechanism by which Cl-reabsorption accompanies Na+ reabsorption.
Specific Aim I will examine the effect of volume depletion in in vitro studies on the activities of the H+-K+ ATPase and CI/HCO-3 exchanger in intercalated cells of cortical collecting tubules, and H+-K+-ATPase abundance and localization in renal cortex homogenate and in fixed kidney from control and volume depleted rats. In vivo studies will be performed on the effects of angiotensin, part of the renin-angiotensin-aldosterone system, which is stimulated in voluime depletion, on H+-K+-ATPase activity and Cl/HCO-3 exchange rate.
Specific Aim II will investigate the role of angiotensin in acutely regulating the function of H+-K+-ATPases and the Cl-/HCO-3 exchanger in intercalated cells in vitro. Two signal transduction pathways associated with the actions of angiotensin will be studied in order to determine how angiotensin exerts its effects on intercalated cell transport. The overall premise for conducting these experiments is that if we understand the physiological basis by which the body normaIly conserves K+, then we will also have identified a target that potentially can be exploited for therapy of disorders of K+ metabolism.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060726-03
Application #
6755023
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Flessner, Michael Francis
Project Start
2002-07-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$285,609
Indirect Cost

  Institution

Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

O'Connor, Nathan; Silver, Randi B (2013) Ratio imaging: practical considerations for measuring intracellular Ca2+ and pH in living cells. Methods Cell Biol 114:387-406
Veerappan, Arul; Reid, Alicia C; O'Connor, Nathan et al. (2012) Mast cells are required for the development of renal fibrosis in the rodent unilateral ureteral obstruction model. Am J Physiol Renal Physiol 302:F192-204
Veerappan, Arul; Reid, Alicia C; Estephan, Racha et al. (2008) Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction. Proc Natl Acad Sci U S A 105:1315-20
Kano, Seiichiro; Tyler, Eleanor; Salazar-Rodriguez, Mariselis et al. (2008) Immediate hypersensitivity elicits renin release from cardiac mast cells. Int Arch Allergy Immunol 146:71-5
Levi, Roberto; Seyedi, Nahid; Schaefer, Ulrich et al. (2007) Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway. Biochem Pharmacol 73:1146-56
O'Connor, Nathan; Silver, Randi B (2007) Ratio imaging: practical considerations for measuring intracellular Ca2+ and pH in living cells. Methods Cell Biol 81:415-33
Reid, Alicia C; Silver, Randi B; Levi, Roberto (2007) Renin: at the heart of the mast cell. Immunol Rev 217:123-40
Mackins, Christina J; Kano, Seiichiro; Seyedi, Nahid et al. (2006) Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 116:1063-70
Seyedi, Nahid; Mackins, Christina J; Machida, Takuji et al. (2005) Histamine H3-receptor-induced attenuation of norepinephrine exocytosis: a decreased protein kinase a activity mediates a reduction in intracellular calcium. J Pharmacol Exp Ther 312:272-80
Silver, Randi B; Reid, Alicia C; Mackins, Christina J et al. (2004) Mast cells: a unique source of renin. Proc Natl Acad Sci U S A 101:13607-12

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