DHHC21 deficiency attenuates renal dysfunction during septic injury

Abstract Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltra...

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Autores principales:	Xiaoyuan Yang, Ethan Zheng, Yonggang Ma, Victor Chatterjee, Nuria Villalba, Jerome W. Breslin, Ruisheng Liu, Mack H. Wu, Sarah Y. Yuan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64fd8b2390c941cda9dee29062fc04ea
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spelling	oai:doaj.org-article:64fd8b2390c941cda9dee29062fc04ea2021-12-02T16:53:11ZDHHC21 deficiency attenuates renal dysfunction during septic injury10.1038/s41598-021-89983-x2045-2322https://doaj.org/article/64fd8b2390c941cda9dee29062fc04ea2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89983-xhttps://doaj.org/toc/2045-2322Abstract Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient (Zdhhc21 dep/dep ) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21 dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21 dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21 dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.Xiaoyuan YangEthan ZhengYonggang MaVictor ChatterjeeNuria VillalbaJerome W. BreslinRuisheng LiuMack H. WuSarah Y. YuanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaoyuan Yang Ethan Zheng Yonggang Ma Victor Chatterjee Nuria Villalba Jerome W. Breslin Ruisheng Liu Mack H. Wu Sarah Y. Yuan DHHC21 deficiency attenuates renal dysfunction during septic injury
description	Abstract Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient (Zdhhc21 dep/dep ) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21 dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21 dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21 dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.
format	article
author	Xiaoyuan Yang Ethan Zheng Yonggang Ma Victor Chatterjee Nuria Villalba Jerome W. Breslin Ruisheng Liu Mack H. Wu Sarah Y. Yuan
author_facet	Xiaoyuan Yang Ethan Zheng Yonggang Ma Victor Chatterjee Nuria Villalba Jerome W. Breslin Ruisheng Liu Mack H. Wu Sarah Y. Yuan
author_sort	Xiaoyuan Yang
title	DHHC21 deficiency attenuates renal dysfunction during septic injury
title_short	DHHC21 deficiency attenuates renal dysfunction during septic injury
title_full	DHHC21 deficiency attenuates renal dysfunction during septic injury
title_fullStr	DHHC21 deficiency attenuates renal dysfunction during septic injury
title_full_unstemmed	DHHC21 deficiency attenuates renal dysfunction during septic injury
title_sort	dhhc21 deficiency attenuates renal dysfunction during septic injury
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/64fd8b2390c941cda9dee29062fc04ea
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DHHC21 deficiency attenuates renal dysfunction during septic injury

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