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Abstract: FR-OR29

PRDM16 Protected Tubular Mitochondrial Function and Attenuated Renal Fibrosis by Upregulating PGC-1α

Session Information

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Yuan, Qian, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Tang, Ben, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Zhang, Chun, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Background

The kidney is a high oxygen consumption organ with abundant mitochondria. However, in the kidney of chronic kidney disease (CKD) patients or animals, mitochondria in tubules were decreased and destroyed. Similarly, brown adipocytes with rich mitochondria converted into white adipocytes with rare mitochondria due to loss of PRDM16. Thus, we proposed that PRDM16 preserved tubular mitochondria and attenuated renal fibrosis.

Methods

Male C57BL/6J mice with 8 weeks were operated with unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion (UIRI) surgery. Kidneys and blood were collected. Western Blot, qPCR, and immunohistochemical staining (IHC) were used to test the expression of PRDM16 in injured kidneys. Lentivirus was used to overexpress PRDM16 in HK2 cells, and UUO and UIRI models. RNA-sequencing, Western Blot, qPCR, IHC, ATP detecting, Oil-red staining, mito-tracker staining, Masson’s staining, renal function detecting, and electron microscope were used to verify the renal protected role of PRDM16 in vivo and in vitro. Tubular-specific PRDM16 knockout mice were generated. PGC-1α agonist ZLN-005, p-Smad3 inhibitor SIS3, DNA-pull down, ChIP, Co-IP, and luciferase assay were used to verify the mechanism of PRDM16.

Results

The results showed PRDM16 was largely expressed by tubular epithelial cells of healthy kidneys, but decreased greatly in injured kidneys. TGF-β mediated the depression of PRDM16 in Smad3 dependent way. PRDM16 overexpression inhibited TGF-β induced mitochondrial dysfunction and restored PGC-1α levels in vitro. And PRDM16 attenuated renal fibrosis, and preserved mitochondrial function and PGC-1α levels in UUO and UIRI models. However, the kidney injury was worse in PRDM16 tubular-specific knockout mice who suffered from UUO and UIRI surgery, and the effects can be attenuated by the PGC-1α agonist, ZLN-005. Mechanistically, PRDM16 upregulated the expression of PGC-1α by directly binding to the promoter of PGC-1α.

Conclusion

PRDM16 was highly expressed by normal tubular epithelial cells but decreased greatly in injured kidneys. The downregulation of PRDM16 was mediated by TGF-β in Smad3 dependent way. PRDM16 overexpression attenuated renal fibrosis and protected tubular mitochondrial function. Mechanistically, PRDM16 upregulated the expression of PGC-1α by directly binding to the promoter of PGC-1α.

Funding

  • Government Support – Non-U.S.