The long-range goal of this research is to examine the role of H,K-ATPases in potassium homeostasis and to determine how these ion-motive pumps are regulated by ion channels. H,K-ATPases are important for renal potassium conservation, but it is now apparent that the kidney possesses several different H,K-ATPase enzymatic activities which likely reflect the presence of multiple gene products. Experiments in Specific Aim 1 will determine the molecular identities of the H,K-ATPase subunit isoforms that are responsible for specific enzymatic activities, and for potassium and proton flux in discrete nephron segments, by the study of animals with targeted gene disruption of the H,K-ATPase HK-alpha-1, HK-alpha-2, or HK-beta genes. Experiments in Specific Aim 2 will examine whether knockout of HK-alpha-1, HK-alpha-2, or HK-beta subunits affects the normal anatomy of the kidney or the morphological response to potassium depletion. Experiments in Specific Aim 3 will characterize fully the newly discovered potassium-permeable ion channels that are present at the apical membrane of the inner stripe of the outer medullary collecting duct (OMCD), and the cell types that contain these channels. These channels exhibit novel properties since they appear to be stimulated by cellular acidification whereas most potassium channels are inhibited by acidosis. The proposed experiments are intended to establish the contribution of each of these genes to an important adaptive response (potassium depletion), the compensatory renal response to the disruption of these genes, and whether these genes are involved in the normal morphology of the kidney or its response to potassium depletion. Since accruing evidence indicates that modest potassium depletion causes or contributes to systemic arterial hypertension, and may contribute to chronic renal insufficiency, these studies area expected to contribute to our understanding of the role of potassium depletion as a risk factor for both renal and cardiovascular disease.
| Greenlee, Megan M; Lynch, I Jeanette; Gumz, Michelle L et al. (2011) Mineralocorticoids stimulate the activity and expression of renal H+,K+-ATPases. J Am Soc Nephrol 22:49-58 |
| Greenlee, Megan M; Lynch, Irma Jeanette; Gumz, Michelle L et al. (2010) The renal H,K-ATPases. Curr Opin Nephrol Hypertens 19:478-82 |
| Shao, Jiahong; Gumz, Michelle L; Cain, Brian D et al. (2010) Pharmacological profiles of the murine gastric and colonic H,K-ATPases. Biochim Biophys Acta 1800:906-11 |
| Gumz, Michelle L; Cheng, Kit-Yan; Lynch, I Jeanette et al. (2010) Regulation of ?ENaC expression by the circadian clock protein Period 1 in mpkCCD(c14) cells. Biochim Biophys Acta 1799:622-9 |
| Lynch, I Jeanette; Greenlee, Megan M; Gumz, Michelle L et al. (2010) Heterogeneity of H-K-ATPase-mediated acid secretion along the mouse collecting duct. Am J Physiol Renal Physiol 298:F408-15 |
| Gumz, Michelle L; Lynch, I Jeanette; Greenlee, Megan M et al. (2010) The renal H+-K+-ATPases: physiology, regulation, and structure. Am J Physiol Renal Physiol 298:F12-21 |
| Stow, Lisa R; Gumz, Michelle L; Lynch, I Jeanette et al. (2009) Aldosterone modulates steroid receptor binding to the endothelin-1 gene (edn1). J Biol Chem 284:30087-96 |
| Greenlee, Megan; Wingo, Charles S; McDonough, Alicia A et al. (2009) Narrative review: evolving concepts in potassium homeostasis and hypokalemia. Ann Intern Med 150:619-25 |
| Gumz, Michelle L; Stow, Lisa R; Lynch, I Jeanette et al. (2009) The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice. J Clin Invest 119:2423-34 |
| Lynch, I Jeanette; Rudin, Alicia; Xia, Shen-Ling et al. (2008) Impaired acid secretion in cortical collecting duct intercalated cells from H-K-ATPase-deficient mice: role of HKalpha isoforms. Am J Physiol Renal Physiol 294:F621-7 |
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