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Abstract: SA-OR021

Decreased KAT5 Expression Impairs DNA Repair and Induces DNA Methylation in Diabetic Nephropathy Podocytes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hishikawa, Akihito, Keio University School of Medicine, Tokyo, Japan
  • Hayashi, Kaori, Keio University School of Medicine, Tokyo, Japan
  • Yoshimoto, Norifumi, Keio University School of Medicine, Tokyo, Japan
  • Itoh, Hiroshi, Keio University School of Medicine, Tokyo, Japan
Background

Podocytes are terminally differentiated cells with a very low capacity of regeneration. Therefore, the mechanism of DNA damage repair in podocytes is expected to be highly significant. We have recently reported that podocyte specific deletion of DNA double strand break (DSB) repair factor KAT5 causes glomerulosclerosis in mice (KAT5 KO mice) (ASN Kidney week 2017). Here we investigated the role of KAT5 in the pathogenesis of diabetic nephropathy (DN).

Methods

We generated tamoxifen-inducible podocyte-specific KAT5 knockout mice (iKO) to investigate the physiological role of KAT5 excluding its role in the maturation of podocytes. Expression of KAT5 was examined in streptozotocin (STZ)-induced DN mice model and the effect of KAT5 gene transfer was evaluated. We performed in vitro studies using cultured human podocytes to examine the mechanism of KAT5-associated epigenetic changes.

Results

KAT5 iKO mice showed massive albuminuria (WT 40±9 mg/gCr, iKO 2455±153 mg/gCr, p<0.01) and FSGS lesion with foot process effacement of podocytes after 12 weeks induction of KAT5 knockdown, similar to the KAT5 KO mice. Nephrin expression was significantly decreased, as shown by both isolated podocytes and glomerular immunofluorescence staining. Interestingly, thickening of glomerular basement membrane was observed in some glomeruli of KAT5 iKO mice just like in DN, which was observed especially in the glomeruli near the corticomedullary junction. Podocyte KAT5 expression was decreased in DN mice, accompanied by increased DNA DSBs and DNA methylation and restoration of decreased KAT5 by gene transfer attenuated albuminuria and glomerulosclerosis. In cultured human podocytes, knockdown of KAT5 increased DNA DSBs and decreased nephrin expression with increased DNA methylation of the nephrin promoter region. High-glucose treatment (30mM) induced KAT5 reduction and overexpression of KAT5 increased nephrin expression with decreased DNA DSBs and decreased DNA methylation at the same nephrin promoter region, indicating that KAT5-mediated DNA repair may be related to the DNA methylation status.

Conclusion

KAT5-mediated DNA repair is essential for podocyte maintenance and has relation to the changes in DNA methylation status in DN. KAT5 may be a good therapeutic target for DN.