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Abstract: SA-PO237

The Molecular Effect of Empagliflozin (SGLT2i) on the Autophagy Pathway in Type 2 Diabetic Mice Model With Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Nakhoul, Farid M., Cardiovascular research lab The Galilee Medical Center, Nahariya, Israel
  • Ertracht, Offir, Cardiovascular research institute The galilee medical Center, Nahariya, Israel
  • Nakhoul, Nakhoul, Ophtalmology Division, baruch Padeh Poriya medical Center, Lower galilee, Israel
  • Tadmor, Hagar, Diabetes and Metabolism Lab, Baruch Padeh Poriya Medical Center, Tiberias, Israel
Background

Diabetes mellitus (DM) type II (Hyperglycemia), is associated with increased glucose cell toxicity and inflammation leading to irreversibl damage to the kidney cells. Autophagy plays a key role in the degradation of damaged intracellular proteins in order to maintain intracellular homeostasis and cell integrity. During DM, their is decreased in the autophagy with consequent development & progression of diabetic nephropathy (DN). Our aim is to investigate the molecular effect of SGLT2i (EMPA) on the expression of ATG5 and its downstream
collaborator LC3-II in DM mice model

Methods

The 8 weeksold male type II DM mice were used: 20 C57BL/6J Wild Type (C57), 20 BTBR ob/ob vehicles (DM), 20 BTBR ob/ob that werereatedwithEMPA
in drinking water
Body weight, urinary &blood glucose were measured at basal & 1 and 2 months. Lysates from murine renal cortex were subjected to histological, immunohistochemically, western blot analysis (WB) and fibrosis(Fibronectin). All mice were sacrificed 13 week after the beginning of the experiment.

Results

At two months, the DM and DM+EMPA mice groups gain weight considerably vs C57/Bl (P>,0.01). Urine output increased as soon as 1 & 2 month of treatment (TX) in DM & DM+EMPA group VS control (P<0.001).
Western blots (WB) significant reduction in ATG5 level in renal lysate of DM mice compared with C57/Bl mice (P< 0.01), Quantification of the WB indicate significant reducedion in ATG5 level in renal lysate of DM mice compared with C57/Bl mice (P< 0.01), and moderate yet non-significant increased by the EMPA TX (P>0.05). ATG5 immunostianing was significantly decreased in DM mice compared with C57/Bl (P<0.001), and significant increased in DM+EMPA mice compared with DM mice (P<0.001.
Renal LC3-II protein level & immunostaining were significantly reduced in DM mice compared with C57/Bl ( P<0.001), and increased levels in DM+EMPA group VS untreated DM mice (P<0.001). Fibronectin level was reduced in DM mice compared to contror and restored toward normal with EMPA TX.

Conclusion

Decrease in ATG5 & LC3-II proteins levels during chronic hyperglycemia (DM) contributes to deficiencies in the autophagy process, with development and progression of DN.
EMPA TX significantly reduce the development & progression of DN in people with type II DM and should be recommended in early stages of the disease.

Funding

  • Government Support – Non-U.S.