Kidney Week

Abstract: FR-PO0245

TRIM28 Promotes Maladaptive Kidney Repair and Fibrosis Through SUMOylation-Dependent Stabilization of ZNF8

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Yang, Dong, University of Connecticut School of Medicine, Farmington, Connecticut, United States

Dong Yang, MD, PhD

• Jiao, Baihai, University of Connecticut School of Medicine, Farmington, Connecticut, United States

Baihai Jiao, PhD

• Tran, Melanie, University of Connecticut School of Medicine, Farmington, Connecticut, United States

Melanie Tran, PhD

• Wang, Yanlin, University of Connecticut School of Medicine, Farmington, Connecticut, United States

Yanlin Wang, MD, PhD, FASN

Background

Chronic kidney disease (CKD) is a progressive disorder characterized by tubular atrophy, inflammation, and tubulointerstitial fibrosis leading to nephron loss and declining kidney function. Tubular epithelial cell (TEC) dedifferentiation, G2/M cell cycle arrest, and cellular senescence are central drivers of maladaptive repair, resulting in the production of proinflammatory and profibrotic mediators, inflammation, and interstitial fibrosis. However, the molecular mechanisms of TEC dedifferentiation, G2/M cell cycle arrest, and cellular senescence remain poorly defined. Here, we investigated the role and mechanisms of tripartite-motif-containing protein 28 (TRIM28) in tubular dedifferentiation, G2/M cell-cycle arrest, senescence, and kidney fibrosis.

Methods

Tamoxifen-inducible global TRIM28 knockout (Trim28^GKO) mice and tubule-specific TRIM28 knockout (Trim28^TKO) mice were generated by crossing TRIM28 floxed mice with CAG-Cre mice and KSP-Cre mice, respectively. Littermate Trim28^fl/fl mice were used as controls. The CKD mouse model was induced by unilateral ureteral obstruction (UUO, day 10) or folic acid nephropathy (FA, 250 mg/kg, day 14). Kidneys were collected for analysis of TEC dedifferentiation, G2/M cell cycle arrest, cellular senescence, and fibrotic markers. Proteomics was used to identify potential interaction partners of TRIM28. Cultured TECs were used to examine the roles of Trim28 and zinc finger protein 8 (ZNF8) in regulating G2/M cell cycle arrest, cellular senescence, dedifferentiation, and fibrosis.

Results

Compared with control mice, both Trim28^GKO and Trim28^TKO markedly attenuated TEC dedifferentiation, G2/M cell-cycle arrest, senescence, and interstitial fibrosis after UUO and FA-induced CKD. Proteomics identified ZNF8 as a novel TRIM28-interacting protein. Mechanistically, TRIM28 promoted ZNF8 stabilization by enhancing ZNF8 SUMOylation and reducing its ubiquitination. In cultured TECs, knockdown of TRIM28 or ZNF8 reduced dedifferentiation, G2/M arrest, senescence, and fibrotic marker expression.

Conclusion

These findings identify the TRIM28/ZNF8 axis as a previously unrecognized regulator of maladaptive tubular responses in CKD. TRIM28-dependent stabilization of ZNF8 promotes tubular dedifferentiation, G2/M arrest, senescence, and kidney fibrosis, suggesting that targeting the TRIM28/ZNF8 axis may represent a potential strategy to treat CKD.

Funding

• NIDDK Support