Zyxin acts as a protective factor in renal tubules during hypertensive nephropathy by restraining FAK/Skp2-CDK8/YAP signaling, and its overexpression significantly improved renal function and attenuated tubulointerstitial injury independently of blood pressure changes.
Key Findings
Results
Zyxin was significantly downregulated in renal tubules of hypertensive nephropathy mice and Ang II-treated HK-2 cells.
A multi-hit DOCA/Ang II + uninephrectomy + high salt approach was used to establish the HN murine model.
In vitro, HK-2 cells (human proximal tubular epithelial cells) were stimulated with Ang II to replicate hypertensive conditions.
Zyxin downregulation was observed specifically in the renal tubular compartment.
Zyxin reduction was mechanistically linked to Ang II-induced calpain activation.
Results
Zyxin overexpression significantly improved renal function and attenuated tubulointerstitial injury in the HN model.
Intrarenal zyxin was overexpressed using adeno-associated virus (AAV) delivery.
Zyxin overexpression resulted in a representative reduction of approximately 40% in the expression of fibrotic markers.
Both renal inflammation and interstitial fibrosis were attenuated upon zyxin overexpression.
Renal function was evaluated through biochemical assays and molecular signaling analysis.
Results
The protective effects of zyxin overexpression on renal function occurred independently of blood pressure changes.
Blood pressure was monitored as part of the experimental evaluation.
Improvement in renal function and reduction of tubulointerstitial injury were observed without corresponding changes in blood pressure.
This finding suggests zyxin's renoprotective role is a direct intrarenal effect rather than a systemic hemodynamic effect.
The independence from blood pressure changes was noted as a key mechanistic distinction.
Results
Zyxin depletion disinhibits the FAK/Skp2 axis and enhances CDK8/YAP signaling, contributing to renal inflammation and interstitial fibrosis.
Zyxin, as a focal adhesion protein, normally restrains FAK (focal adhesion kinase) activity.
Loss of zyxin led to activation of the FAK/Skp2 signaling axis.
Enhanced CDK8/YAP signaling downstream was identified as a potential contributor to both inflammation and fibrosis.
The mechanistic pathway was characterized as: Ang II → calpain activation → zyxin degradation → FAK/Skp2 disinhibition → CDK8/YAP activation → tubulointerstitial injury.
Zyxin levels were modulated in vitro via lentiviral transduction to confirm the mechanistic relationship.
Results
Ang II-induced calpain activation is the upstream mechanism responsible for zyxin reduction in hypertensive nephropathy.
Calpain, a calcium-dependent protease, was activated in response to Ang II stimulation.
Calpain activation was linked to subsequent zyxin proteolytic degradation in tubular epithelial cells.
This mechanism connects the hypertensive stimulus (Ang II) to the focal adhesion protein loss observed in HN.
The calpain-zyxin link was identified in both the in vivo HN model and Ang II-treated HK-2 cells.
Conclusions
Zyxin is proposed as a novel therapeutic target for hypertensive nephropathy-induced tubulointerstitial injury.
Tubulointerstitial fibrosis and inflammation are described as hallmark pathological features of hypertensive nephropathy.
Prior to this study, zyxin had been implicated in hypertension-related pathologies but its specific role in HN-induced tubulointerstitial injury was undefined.
The findings support a model in which zyxin acts as a protective factor in renal tubules during HN.
The authors suggest zyxin's potential as a novel therapeutic target based on the mechanistic and functional data.
What This Means
This research investigates why the kidneys become damaged in people with hypertension (high blood pressure), focusing on a protein called zyxin found in kidney tubule cells. The researchers created a mouse model of hypertensive kidney disease and found that zyxin levels dropped significantly in the kidney tubules when exposed to the stress hormone angiotensin II (Ang II), which plays a major role in high blood pressure. They discovered that Ang II activates an enzyme called calpain, which breaks down zyxin. When zyxin levels fall, a chain reaction of harmful cell signaling (through FAK, Skp2, CDK8, and YAP proteins) is unleashed, leading to kidney inflammation and scarring (fibrosis).
When the researchers artificially restored zyxin levels in the kidneys using gene therapy (via adeno-associated virus), the mice showed significantly improved kidney function and about 40% less fibrosis-related protein expression — and importantly, these benefits occurred without any change in blood pressure. This suggests zyxin directly protects kidney cells rather than acting indirectly through blood pressure reduction. The same protective effects were confirmed in human kidney tubule cells grown in the lab.
This research suggests that zyxin loss is a key driver of kidney damage in hypertension, and that restoring or protecting zyxin activity could be a new strategy for treating hypertensive kidney disease. Current treatments for this condition focus heavily on lowering blood pressure, so identifying a target that works independently of blood pressure could open new avenues for kidney protection in patients where blood pressure control alone is insufficient.
Huang W, Chen Y, Wang Y, Du S, Hao Y, Zhang C, et al.. (2026). Zyxin protects against hypertensive nephropathy by restraining FAK/Skp2-CDK8/YAP signaling in tubular epithelial cells.. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. https://doi.org/10.1007/s00011-026-02373-9