DHHC21 Deficiency Attenuates Renal Dysfunction During Septic Injury release_gxopecgsdbfgpihm4ouj7wjnpa

Abstract

<jats:title>Abstract</jats:title> 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 (<jats:italic>Zdhhc21</jats:italic><jats:sup><jats:italic>dep/dep</jats:italic></jats:sup>) 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 <jats:italic>Zdhhc21</jats:italic><jats:sup><jats:italic>dep/dep</jats:italic></jats:sup> mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in <jats:italic>Zdhhc21</jats:italic><jats:sup><jats:italic>dep/dep</jats:italic></jats:sup> mice. Vasoreactivity analysis revealed that renal arteries from <jats:italic>Zdhhc21</jats:italic><jats:sup><jats:italic>dep/dep</jats:italic></jats:sup> 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.
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