Browsing by Subject "Angiotensin II / pharmacology"
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Item Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice(Springer Nature, 2017-06-23) Li, Weizu; Ding, Yanfeng; Smedley, Crystal; Wang, Yanxia; Chaudhari, Sarika; Birnbaumer, Lutz; Ma, RongThe present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific shRNA construct significantly attenuated Ang II-induced GFR decline in rats. Furthermore, Ang II-stimulated contraction and Ca(2+) entry were significantly suppressed in primary MCs isolated from TRPC6 deficient mice, and the Ca(2+) response could be rescued by re-introducing TRPC6. Moreover, inhibition of reverse mode of Na(+)-Ca(2+) exchange by KB-R7943 significantly reduced Ca(2+) entry response in TRPC6-expressing, but not in TRPC6-knocked down MCs. Ca(2+) entry response was also significantly attenuated in Na(+) free solution. Single knockdown of TRPC6 and TRPC1 resulted in a comparable suppression on Ca(2+) entry with double knockdown of both. These results suggest that TRPC6 may regulate GFR by modulating MC contractile function through multiple Ca(2+) signaling pathways.Item Selectively Inhibiting the Median Preoptic Nucleus Attenuates Angiotensin II and Hyperosmotic-Induced Drinking Behavior and Vasopressin Release in Adult Male Rats(Society for Neuroscience, 2019-03-26) Marciante, Alexandria B.; Wang, Lei A.; Farmer, George E.; Cunningham, J. ThomasThe median preoptic nucleus (MnPO) is a putative integrative region that contributes to body fluid balance. Activation of the MnPO can influence thirst, but it is not clear how these responses are linked to body fluid homeostasis. We used designer receptors exclusively activated by designer drugs (DREADDs) to determine the role of the MnPO in drinking behavior and vasopressin release in response to peripheral angiotensin II (ANG II) or 3% hypertonic saline (3% HTN) in adult male Sprague Dawley rats (250-300 g). Rats were anesthetized with isoflurane and stereotaxically injected with an inhibitory DREADD (rAAV5-CaMKIIa-hM4D(Gi)-mCherry) or control (rAAV5-CaMKIIa-mCherry) virus in the MnPO. After two weeks' recovery, a subset of rats was used for extracellular recordings to verify functional effects of ANG II or hyperosmotic challenges in MnPO slice preparations. Remaining rats were used in drinking behavior studies. Each rat was administered either 10 mg/kg of exogenous clozapine-N-oxide (CNO) to inhibit DREADD-expressing cells or vehicle intraperitoneal followed by a test treatment with either 2-mg/kg ANG II or 3% HTN (1 ml/100-g bw, s.c.), twice per week for two separate treatment weeks. CNO-induced inhibition during either test treatment significantly attenuated drinking responses compared to vehicle treatments and controls. Brain tissue processed for cFos immunohistochemistry showed decreased expression with CNO-induced inhibition during either test treatment in the MnPO and downstream nuclei compared to controls. CNO-mediated inhibition significantly attenuated treatment-induced increases in plasma vasopressin compared to controls. The results indicate inhibition of CaMKIIa-expressing MnPO neurons significantly reduces drinking and vasopressin release in response to ANG II or hyperosmotic challenge.