DHHC21 deficiency attenuates renal dysfunction during septic injury

• Published in: Scientific reports 2021-05, Vol.11 (1), p.11146-11146, Article 11146
• Main Authors: Yang, Xiaoyuan, Zheng, Ethan, Ma, Yonggang, Chatterjee, Victor, Villalba, Nuria, Breslin, Jerome W., Liu, Ruisheng, Wu, Mack H., Yuan, Sarah Y.
• Format: Article
• Language: English
• Subjects: 631/443/1338; 631/443/272; 631/80/458; 692/699/255; Acyltransferases - genetics; Animals; Cecum - metabolism; Cecum - physiopathology; Humanities and Social Sciences; Kidney - metabolism; Kidney - physiopathology; Kidney Diseases - etiology; Kidney Diseases - genetics; Kidney Diseases - physiopathology; Lipoylation; Mice; Mice, Knockout; multidisciplinary; Receptors, Adrenergic, alpha-1 - metabolism; Science; Science (multidisciplinary); Sepsis - complications; Sepsis - genetics; Sepsis - physiopathology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-89983-x

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.