Empagliflozin improves diabetic renal tubular injury by alleviating
mitochondrial fission via AMPK/SP1/PGAM5 pathway.
Background and Purpose: Excessive mitochondrial fission was observed in
diabetic kidney disease (DKD). Phosphoglycerate mutase family member 5
(PGAM5) plays an important role in mitochondrial fission by
dephosphorylating the DRP1S637. Whether PGAM5 participates in the
mitochondrial fission in diabetic renal tubular injury is unknown.
Clinical trials have observed encouraging effect of Sodium-glucose
cotransporter 2 (SGLT2) inhibitors on DKD though the underling
mechanisms remain unclear. Experimental Approach: We use KK-Ay mice as
diabetic model and Empa was administrated by oral gavage. The
mitochondrial fission and expressions of p-AMPK, SP1, PGAM5 and
DRP1-S637 were tested. We also examined these changes in HK2 cells that
cultured in normal glucose (NG), high glucose (HG) and high glucose+Empa
(HG+Empa) environment. Then we verified our deduction using AMPK
activator, inhibitor, si-SP1 and si-PGAM5. Lastly, we testified the
interaction between SP1 and the PGAM5promotor by CHIP assay. Key
Results: The mitochondrial fission and the expression of SP1, PGAM5
increased and the expression of p-AMPK, DRP1-S637 decreased in diabetic
or HG environment. These changes were all reversed in Empa or AICAR
treated groups. These reversal effect of Empa could be diminished by
Compound C. Either si-SP1 or si-PGAM5 could alleviated the mitochondrial
fission without affection on AMPK phosphorylation. Finally, the CHIP
assay confirmed the interaction between SP1 and the PGAM5 promotor.
Conclusions and Implications: The PGAM5 aggravates the development of
diabetic renal tubular injury and the Empa can improve the DKD by
alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway.