Type B intercalated cells are expressed within the cortical collecting duct (CCD) and the connecting tubule (CNT), where they act to secrete HCO3- and absorb Cl- across the apical plasma membrane, through the Cl-/HCO3- exchanger, pendrin. Pendrin-mediated HCO3- secretion reduces arterial pH and HCO3- concentration, which contributes to the correction of a metabolic alkalosis. Moreover, pendrin-mediated Cl- absorption augments vascular volume, which raises blood pressure. Since pendrin is regulated by aldosterone and angiotensin II and since many of the effects of aldosterone and angiotensin II are mediated by changes in nitric oxide availability, we will test the hypothesis that nitric oxide (NO) modulates pendrin abundance and function through cyclic nucleotide-dependent pathways. Published and preliminary data show that nitric oxide reduces HCO3- secretion and Cl- absorption within the CCD, which most likely occurs in part by inhibiting pendrin-mediated Cl-/HCO3- exchange. Our preliminary data show that with longer-term exposure to the nitric oxide synthase inhibitor, L-NAME, pendrin abundance increases both in vivo and in vitro. These data support the hypothesis that NO modulates pendrin abundance and function. We hypothesize that nitric oxide acts on pendrin abundance and function primarily by reducing cAMP availability. The purpose of this proposal is to characterize the effect of nitric oxide on Cl- absorption and HCO3- secretion in the CCD and to determine the transport mechanism and the signaling pathway by which this occurs. We will also examine the mechanism by which nitric oxide regulates pendrin abundance in vivo and in vitro. These studies will elucidate how Cl- absorption is regulated in the CCD and the CNT and thus how these segments modulate blood pressure. The proposal's specific aims are the following:
Aim 1 : To determine the transport mechanism by which nitric oxide modulates anion transport in mouse CCD in vitro.
Aim 2 : To determine the signaling mechanism through which NO modulates anion transport in vitro in mouse CCD.
Aim 3 : To determine how NO modulates pendrin protein abundance in vitro and in vivo. To accomplish these objectives, the regulation of pendrin abundance and function by NO and the signaling mechanism by which this occurs will be examined in tissue from wild type and genetically modified mice both in vivo and in vitro using using quantitative real time PCR, light microscopic immunohistochemistry, immunogold cytochemistry, immunofluorescence and immunoblots. Transport studies will be performed in renal tubules perfused in vitro.
Our laboratory has observed that a protein called pendrin mediates absorption of chloride by the kidney, which raises blood pressure. Blood pressure is regulated in part by the amount of nitric oxide produced. Moreover, nitric oxide mediates some of the actions of other hormones such as aldosterone and angiotensin II. This project will test the effect of nitric oxide on pendrin abundance and function and determine the mechanism by which nitric oxide regulates pendrin.
|Wall, Susan M (2016) The role of pendrin in blood pressure regulation. Am J Physiol Renal Physiol 310:F193-203|
|West, Crystal A; Verlander, Jill W; Wall, Susan M et al. (2015) The chloride-bicarbonate exchanger pendrin is increased in the kidney of the pregnant rat. Exp Physiol 100:1177-86|
|Nanami, Masayoshi; Lazo-Fernandez, Yoskaly; Pech, Vladimir et al. (2015) ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl- secretion. Am J Physiol Renal Physiol 309:F251-8|
|Lazo-Fernandez, Yoskaly; Aguilera, Greti; Pham, Truyen D et al. (2015) Pendrin localizes to the adrenal medulla and modulates catecholamine release. Am J Physiol Endocrinol Metab 309:E534-45|
|Pech, Vladimir; Wall, Susan M; Nanami, Masayoshi et al. (2015) Pendrin gene ablation alters ENaC subcellular distribution and open probability. Am J Physiol Renal Physiol 309:F154-63|
|Nanami, Masayoshi; Pech, Vladimir; Lazo-Fernandez, Yoskaly et al. (2015) ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. II. Bafilomycin-sensitive H+ secretion. Am J Physiol Renal Physiol 309:F259-68|
|Wall, Susan M; Lazo-Fernandez, Yoskaly (2015) The role of pendrin in renal physiology. Annu Rev Physiol 77:363-78|
|Grimm, P Richard; Lazo-Fernandez, Yoskaly; Delpire, Eric et al. (2015) Integrated compensatory network is activated in the absence of NCC phosphorylation. J Clin Invest 125:2136-50|
|Pech, Vladimir; Thumova, Monika; Dikalov, Sergey I et al. (2013) Nitric oxide reduces Cl? absorption in the mouse cortical collecting duct through an ENaC-dependent mechanism. Am J Physiol Renal Physiol 304:F1390-7|
|Wall, Susan M; Weinstein, Alan M (2013) Cortical distal nephron Cl(-) transport in volume homeostasis and blood pressure regulation. Am J Physiol Renal Physiol 305:F427-38|
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