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.
| Kang, Kyu-Tae; Sullivan, Jennifer C; Pollock, Jennifer S (2018) Superoxide Dismutase Activity in Small Mesenteric Arteries Is Downregulated by Angiotensin II but Not by Hypertension. Toxicol Res 34:363-370 |
| De Miguel, Carmen; Sedaka, Randee; Kasztan, Malgorzata et al. (2018) Tauroursodeoxycholic acid (TUDCA) abolishes chronic high salt-induced renal injury and inflammation. Acta Physiol (Oxf) :e13227 |
| Johnston, Jermaine G; Pollock, David M (2018) Circadian regulation of renal function. Free Radic Biol Med 119:93-107 |
| Guan, Z; Wang, F; Cui, X et al. (2018) Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles. Acta Physiol (Oxf) 222: |
| De Miguel, Carmen; Hamrick, William C; Hobbs, Janet L et al. (2017) Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney. Sci Rep 7:43152 |
| Gohar, Eman Y; Kasztan, Malgorzata; Pollock, David M (2017) Interplay between renal endothelin and purinergic signaling systems. Am J Physiol Renal Physiol 313:F666-F668 |
| Gohar, Eman Y; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Activation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats. Am J Physiol Renal Physiol 311:F260-7 |
| De Miguel, Carmen; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens 25:35-41 |
| Jin, Chunhua; Speed, Joshua S; Pollock, David M (2016) High salt intake increases endothelin B receptor function in the renal medulla of rats. Life Sci 159:144-147 |
| Gohar, Eman Y; Giachini, Fernanda R; Pollock, David M et al. (2016) Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci 159:20-29 |
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