The final regulation of urinary K+ and Na+ excretion is accomplished in the renal cortical collecting duct (CCC). In this segment, urinary Na+ diffuses into principal cells through apical Na+ channels (ENaCs) and is extruded at the basolateral membrane in exchange for uptake of K+ by the Na-K pump. Cell K+ then passively diffuses out of the cell down a favorable electrochemical gradient into the luminal fluid through apical K+-selective (SK) channels. Kidneys of full term neonates efficiently retain urinary K+ and Na+, as is necessary for growth. In contrast to the high rates of net K+ secretion observed in CCDs isolated from adult animals and microperfused in vitro, segments from neonatal animals show no significant K+ transport and a paucity of apical SK channels. Yet, the same neonatal segments possess conducting ENaC channels and absorb Na+ at a rate half that measured in the adult. The focus of this application is to examine the cellular and molecular mechanisms mediating the postnatal activation of apical 5K and ENaC channels, those rate-limiting pathways for K+ and Na+ transport in the CCD. The hypotheses we propose to examine, as they relate to the SK (Specific Aim 1) and Na+ (Specific Aim 2) channel, are focussed first on discerning whether the appearance of conducting channels is regulated by transcription, translation, and/or post-translational processing. Thereafter, we will identify those circulating (adrenal corticosteroids) and cytoplasmic (kinases, Ca2+) factors prevailing early in life that regulate gene and protein expression. ion channel activity, and tubular transport in the developing CCD. These studies will be accomplished using a combination of molecular, electrophysiologic, and functional techniques. The long-term goal of this study is to identify the cellular and molecular mechanisms responsible for the regulation and interaction of Na+ and K+ transport in the principal cell. These studies should help us understand the physiologic basis for inherited and acquired disorders associated with electrolyte imbalance, disorders which carry a high morbidity.
| Kleyman, Thomas R; Kashlan, Ossama B; Hughey, Rebecca P (2018) Epithelial Na+ Channel Regulation by Extracellular and Intracellular Factors. Annu Rev Physiol 80:263-281 |
| 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 |
| Boyd-Shiwarski, Cary R; Shiwarski, Daniel J; Roy, Ankita et al. (2018) Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent. Mol Biol Cell 29:499-509 |
| 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 |
| Webb, Tennille N; Carrisoza-Gaytan, Rolando; Montalbetti, Nicolas et al. (2016) Cell-specific regulation of L-WNK1 by dietary K. Am J Physiol Renal Physiol 310:F15-26 |
| 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 |
| Carrisoza-Gaytan, Rolando; Liu, Yu; Flores, Daniel et al. (2014) Effects of biomechanical forces on signaling in the cortical collecting duct (CCD). Am J Physiol Renal Physiol 307:F195-204 |
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