The collecting duct (CD) endothelin system has emerged as an important regulator of renal Na excretion and systemic blood pressure (BP). CD-derived endothelin-1 (ET-1) exerts a hypotensive effect that is likely due, at least partly, to inhibition of the CD epithelial Na channel (ENaC). CD-derived ET-1 is important in mediating the natriuretic response to extracellular fluid volume (ECFV) expansion and controlling arterial BP; defects in the CD ET-1 system may contribute to hypertension. While the general biology of the CD ET system has been established, there remains much unknown about how this system functions. In particular, key components in critical need of study are: 1) determination if and how ET-1 inhibits CD Na transport;and 2) determination how ECFV status is coupled to CD ET-1 production. Based on preliminary data, the proposed studies will address the following hypotheses;ECFV expansion increases tubule fluid flow rate through the CD. Increased flow increases intracellular Ca concentration [Ca2+] through polycystins-1 and -2. Increased CD [Ca2+] induces signaling pathways causing transcriptional activation of the ET-1 gene. This increases CD ET-1 production and secretion resulting in autocrine activation of most likely the ETB receptor (ETRB), but also possibly the ETA receptor (ETRA). ET-1 binding leads to inhibition of the ENaC through reduction of channel open probability (Po) and possibly apical channel number (N). The effect on Po is due, at least partly, to activation of the c-src/MAPK pathway.
The specific aims for this project include:
Aim 1. Test the hypothesis that flow stimulates CD ET-1 production, and that this effect is exerted by activation of specific cellular signaling pathways, cis-acting elements and trans-activating factors. Accordingly, we will: a) determine the effects of flow on CD ET-1 production;and b) determine the cellular signaling pathways, cis-acting elements and trans-activating factors coupling flow and intracellular Ca to ET- 1 gene transcription.
Aim 2. Test the hypothesis that ET-1 regulates ENaC in the CD, and that specific cellular and molecular mechanisms underpin this regulation. Accordingly, we will: a) determine if ET-1 regulates ENaC Po in native isolated CD cells;b) identify the specific ET receptor involved in regulating ENaC in native CD cells and elucidate the cellular signaling pathway coupling this receptor to the channel;c) define the importance of ET- 1 regulation of CD ENaC in physiologic control of renal Na handling, and probe pathophysiological consequences of disrupting this regulation using gene targeted mice;and d) define the molecular mechanisms by which ET-1 modulates ENaC function, including identifying the specific residues/regions of ENaC that enable the channel to respond to ET-1.
This project elucidates mechanisms by which the kidney endothelin system responds to the volume status of the body as well as how elaboration of such renal endothelin leads to regulation of tubular sodium reabsorption. Determination of these pathways will lead to enhanced understanding of how extracellular fluid volume status is regulated and ultimately how systemic blood pressure is controlled.
|Osmond, David A; Zhang, Shali; Pollock, Jennifer S et al. (2014) Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. Am J Physiol Renal Physiol 306:F619-28|
|Pollock, David M (2014) 2013 Dahl Lecture: American Heart Association council for high blood pressure research clarifying the physiology of endothelin. Hypertension 63:e110-7|
|Fellner, Robert C; Cook, Anthony K; O'Connor, Paul M et al. (2014) High-salt diet blunts renal autoregulation by a reactive oxygen species-dependent mechanism. Am J Physiol Renal Physiol 307:F33-40|
|Kohan, Donald E; Barton, Matthias (2014) Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int 86:896-904|
|Guan, Zhengrong; Singletary, Sean T; Cook, Anthony K et al. (2014) Sphingosine-1-phosphate evokes unique segment-specific vasoconstriction of the renal microvasculature. J Am Soc Nephrol 25:1774-85|
|Hyndman, Kelly A; Ho, Dao H; Sega, Martiana F et al. (2014) Histone deacetylase 1 reduces NO production in endothelial cells via lysine deacetylation of NO synthase 3. Am J Physiol Heart Circ Physiol 307:H803-9|
|Donato, Anthony J; Lesniewski, Lisa A; Stuart, Deborah et al. (2014) Smooth muscle specific disruption of the endothelin-A receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development. Life Sci 118:238-43|
|Jin, Chunhua; Jeon, Yejoo; Kleven, Daniel T et al. (2014) Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome. J Pharmacol Exp Ther 351:467-73|
|Kittikulsuth, W; Sullivan, J C; Pollock, D M (2013) ET-1 actions in the kidney: evidence for sex differences. Br J Pharmacol 168:318-26|
|Hyndman, Kelly A; Xue, Jing; MacDonell, Alexander et al. (2013) Distinct regulation of inner medullary collecting duct nitric oxide production from mice and rats. Clin Exp Pharmacol Physiol 40:233-9|
Showing the most recent 10 out of 26 publications