Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease
Authors' conclusion
Our findings uncover a novel Klotho/PKCα/ETS1/CYB5R4 signaling axis in PTECs that restores mitochondrial function and mitigates DKD progression
Study context
- Population
- Human kidney biopsies from patients at different diabetic kidney disease (DKD) stages; diabetic mouse model; Human kidney (HK-2) cells
- Outcome
- Klotho effect on PTEC mitochondrial function in DKD
Methodological detailshuman kidney biopsies, diabetic mouse model (high-fat diet and streptozotocin), HK-2 cells, knockdown and overexpression
- Human kidney biopsies
- Diabetic mouse model (high-fat diet and streptozotocin)
- HK-2 cells
- Knockdown and overexpression
Main finding
As reported in the abstract
- Klotho alleviates early tubular injury in DKD by targeting the mitochondrial protein CYB5R4
- CYB5R4 is critically downregulated in DKD; its restoration is necessary and sufficient for Klotho's protective effect on mitochondrial function in proximal tubule epithelial cells (PTECs)
- Klotho suppresses PKCα, which inhibits ETS1; ETS1 inhibition de-represses the CYB5R4 promoter, reducing tubular apoptosis and injury
Original publication
Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease. Cardiovasc Diabetol. Published 28 March 2026. doi:10.
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