Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes.

The Journal of Biological Chemistry
Hak Joo LeeBalakuntalam S Kasinath

Abstract

Diabetes-induced kidney cell injury involves an increase in matrix protein expression that is only partly alleviated by current treatment, prompting a search for new modalities. We have previously shown that hydrogen sulfide (H2S) inhibits high glucose-induced protein synthesis in kidney podocytes. We tested whether tadalafil, a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, ameliorates high glucose stimulation of matrix proteins by generating H2S in podocytes. Tadalafil abrogated high glucose stimulation of global protein synthesis and matrix protein laminin γ1. Tadalafil inhibited high glucose-induced activation of mechanistic target of rapamycin complex 1 and laminin γ1 accumulation in an AMP-activated protein kinase (AMPK)-dependent manner. Tadalafil increased AMPK phosphorylation by stimulating calcium-calmodulin kinase kinase β. Tadalafil rapidly increased the expression and activity of the H2S-generating enzyme cystathionine γ-lyase (CSE) by promoting its translation. dl-Propargylglycine, a CSE inhibitor, and siRNA against CSE inhibited tadalafil-induced AMPK phosphorylation and abrogated the tadalafil effect on high glucose stimulation of laminin γ1. In tadalafil-treated podocytes, we examined the int...Continue Reading

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Citations

Sep 2, 2015·Nitric Oxide : Biology and Chemistry·Serap GurWayne J G Hellstrom
Oct 21, 2016·Antioxidants & Redox Signaling·Denis FeliersBalakuntalam S Kasinath
Jul 18, 2017·Antioxidants & Redox Signaling·David D RobertsJeffrey S Isenberg
Oct 16, 2018·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Hak Joo LeeBalakuntalam S Kasinath
Mar 8, 2019·Biological & Pharmaceutical Bulletin·Hua ShenGuojun Wang
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Apr 15, 2016·American Journal of Physiology. Renal Physiology·Małgorzata KasztanMaciej Jankowski
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Dec 20, 2019·Chinese Medical Journal·Yu WangQiong-Jing Yuan
May 3, 2018·GeroScience·Hak Joo LeeBalakuntalam S Kasinath
Nov 6, 2015·American Journal of Physiology. Renal Physiology·Utpal Sen, Sathnur Pushpakumar
Apr 11, 2018·Antioxidants & Redox Signaling·Christopher HineJames R Mitchell
Aug 9, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hai-Jian SunJin-Song Bian
Jan 6, 2021·JCI Insight·Hak Joo LeeBalakuntalam S Kasinath
Dec 29, 2020·Frontiers in Pharmacology·Ebenezeri Erasto NgowiDong-Dong Wu
Mar 24, 2021·Clinical and Experimental Nephrology·Enis Rauf Coskuner, Burak Ozkan
Nov 6, 2020·Cellular Signalling·Karl-Friedrich Beck, Josef Pfeilschifter

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