Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026
Zyxin protects against hypertensive nephropathy by restraining FAK/Skp2-CDK8/YAP signaling in tubular epithelial cells.
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Huang Wei, Chen Yi-Yuan, Wang Yu-Mei, Du Si-Jia, Hao Yu, Zhang Chun, Zhang Xiao-Li, He Fang-Fang
Аннотация
BACKGROUND: Tubulointerstitial fibrosis and inflammation are hallmark pathological features of hypertensive nephropathy (HN), yet the underlying molecular mechanisms remain elusive. Zyxin, a focal adhesion protein, has been implicated in hypertension-related pathologies, but its specific role in HN-induced tubulointerstitial injury remains undefined.
METHODS: An HN murine model was established via a multi‑hit DOCA/Ang II + uninephrectomy + high salt approach. Intrarenal zyxin was overexpressed using adeno-associated virus. In vitro, HK-2 cells were stimulated with Ang II, and zyxin levels were modulated via lentiviral transduction. Renal function, inflammation, and fibrosis were evaluated through biochemical assays and molecular signaling analysis.
RESULTS: Zyxin was significantly downregulated in the renal tubules of HN mice and Ang II-treated HK-2 cells. Zyxin overexpression significantly improved renal function and attenuated tubulointerstitial injury, with a representative reduction of approximately 40% in the expression of fibrotic markers. These protective effects occurred independently of blood pressure changes. Mechanistically, zyxin reduction is linked to Ang II-induced calpain activation. The resulting zyxin depletion potentially disinhibits the FAK/Skp2 axis and enhances CDK8/YAP signaling, which may contribute to renal inflammation and interstitial fibrosis.
CONCLUSIONS: These findings support a model in which zyxin acts as a protective factor in the renal tubules during HN, suggesting its potential as a novel therapeutic target.
METHODS: An HN murine model was established via a multi‑hit DOCA/Ang II + uninephrectomy + high salt approach. Intrarenal zyxin was overexpressed using adeno-associated virus. In vitro, HK-2 cells were stimulated with Ang II, and zyxin levels were modulated via lentiviral transduction. Renal function, inflammation, and fibrosis were evaluated through biochemical assays and molecular signaling analysis.
RESULTS: Zyxin was significantly downregulated in the renal tubules of HN mice and Ang II-treated HK-2 cells. Zyxin overexpression significantly improved renal function and attenuated tubulointerstitial injury, with a representative reduction of approximately 40% in the expression of fibrotic markers. These protective effects occurred independently of blood pressure changes. Mechanistically, zyxin reduction is linked to Ang II-induced calpain activation. The resulting zyxin depletion potentially disinhibits the FAK/Skp2 axis and enhances CDK8/YAP signaling, which may contribute to renal inflammation and interstitial fibrosis.
CONCLUSIONS: These findings support a model in which zyxin acts as a protective factor in the renal tubules during HN, suggesting its potential as a novel therapeutic target.