The magnitude of K+ secretion in the cortical collecting duct (CCD) is determined by its electrochemical gradient and the permeability of the apical membrane to K+. Two apical K+-selective channels have been identified by patch clamp analysis of the fully differentiated CCD. Whereas the secretory K+ (SK) channel, encoded by ROMK, is considered to mediate baseline K+ secretion, the role of the stretch-/Ca2+-activated maxi-K channel, closed at the resting membrane potential, remains uncertain. Two observations suggest that channels other than ROMK contribute to urinary K+ secretion. First, patients with Bartter's syndrome due to loss-of-function mutations in ROMK have modest hypokalemia and not hyperkalemia, as might be expected in the absence of functional SK channels. Second, the developmental appearance of baseline net K+ secretion in the rabbit CCD precedes that of flow-stimulated K+ secretion. In fact, recent data from our lab suggests that flow-dependent K+ secretion is mediated by the maxi-K channel. We hypothesize that the differential expression of alternative spliced transcripts of the maxi-K channel, encoded by slo, that vary in Ca2+ and voltage sensitivity, or in coassembly with regulatory beta subunits, provides a mechanism for modulating flow-dependent K+ secretion in the CCD during normal renal development and the adaptation to disease. To test this, we propose to: (1) define the molecular identity of the renal maxi-K channel subunit isoforms, their functional characteristics, distribution and abundance in the maturing mammalian kidney, and (2) explore the mechanisms by which epigenetic factors, including dietary K+ intake and plasma K+ levels, circulating levels of adrenal corticosteroids and vasopressin regulate maxi-K channel expression and activity. A complementary approach of molecular and functional (in vitro microperfusion and patch clamp analysis) studies is planned. The results of this investigation have broad implications not only in terms of our understanding of the pathophysiology of disease (Bartter's), but also the ontogeny of renal tubular function. Additionally, this study sets the stage for future exploration of the role of biomechanical forces (e.g. flow), via activation of appropriate signal transduction cascades (e.g., Ca2+-associated), in regulation of gene expression as is necessary for normal tubular differentiation and adaptation to disease.
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| Kharade, Sujay V; Kurata, Haruto; Bender, Aaron M et al. (2018) Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992. Mol Pharmacol 94:926-937 |
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| Ray, Evan C; Boyd-Shiwarski, Cary R; Kleyman, Thomas R (2017) Why Diuretics Fail Failing Hearts. J Am Soc Nephrol 28:3137-3138 |
| Carrisoza-Gaytán, Rolando; Wang, Lijun; Schreck, Carlos et al. (2017) The mechanosensitive BK?/?1 channel localizes to cilia of principal cells in rabbit cortical collecting duct (CCD). Am J Physiol Renal Physiol 312:F143-F156 |
| Nizar, Jonathan M; Dong, Wuxing; McClellan, Robert B et al. (2016) Na+-sensitive elevation in blood pressure is ENaC independent in diet-induced obesity and insulin resistance. Am J Physiol Renal Physiol 310:F812-20 |
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| Kharade, Sujay V; Flores, Daniel; Lindsley, Craig W et al. (2016) ROMK inhibitor actions in the nephron probed with diuretics. Am J Physiol Renal Physiol 310:F732-F737 |
| Carrisoza-Gaytan, Rolando; Carattino, Marcelo D; Kleyman, Thomas R et al. (2016) An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron. Am J Physiol Cell Physiol 310:C243-59 |
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