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Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy.
Zhang, Ying; Zhang, Naijin; Zou, Yuanming; Song, Chunyu; Cao, Kexin; Wu, Boquan; You, Shilong; Lu, Saien; Wang, Dong; Xu, Jiaqi; Huang, Xinyue; Zhang, Pengyu; Fan, Zihao; Liu, Jingwei; Cheng, Zhongyi; Zhang, Zhe; Kong, Chuize; Cao, Liu; Sun, Yingxian.
Afiliação
  • Zhang Y; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Zhang N; Institute of Health Sciences, China Medical University (Y.Z., N.Z., Y.S.).
  • Zou Y; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Song C; Institute of Health Sciences, China Medical University (Y.Z., N.Z., Y.S.).
  • Cao K; Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang, China (N.Z.).
  • Wu B; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • You S; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Lu S; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Wang D; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Xu J; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Huang X; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Zhang P; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Fan Z; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Liu J; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Cheng Z; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Zhang Z; Department of Cardiology (Y.Z., N.Z., Y.Z., C.S., K.C., B.W., S.Y., S.L., D.W., J.X., X.H., P.Z., Z.F., Y.S.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
  • Kong C; College of Basic Medical Science; Key Laboratory of Medical Cell Biology, Ministry of Education; Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China (J.L., L.C.).
  • Cao L; Jingjie PTM BioLab Co. Ltd (Z.C.).
  • Sun Y; Department of Urology (Z.Z., C.K.), the First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
Circ Res ; 132(5): 601-624, 2023 03 03.
Article em En | MEDLINE | ID: mdl-36786216
ABSTRACT

BACKGROUND:

Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear.

METHODS:

We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa 26 (Gt(ROSA)26Sor)-SIRT2 (silent mating type information regulation 2 homolog-2)-Flag-TG (transgenic) (SIRT2-TG) mice SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy.

RESULTS:

Using transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)- induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury.

CONCLUSIONS:

Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II-induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Hipertensão / Hipertensão Renal Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Hipertensão / Hipertensão Renal Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article