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Abstract: PO0717

SGLT-2 Inhibition Ameliorates Tubular Injury with Metabolic Suppression in Very Early Phase of Diet-Induced Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Maekawa, Hiroshi, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Kaminski, Dorian, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Fain, Margaret E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Marcheva, Biliana, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Therapies that target the sodium glucose cotransporter 2 (SGLT2) are known to benefit diabetic patients via both metabolic and hemodynamic effects, however, mechanisms promoting renal protection are incompletely known. Here, we investigated the mechanism of reno-protective effects by SGLT2 inhibition in diabetic kidney disease (DKD), focusing on kidney metabolism.

Methods

10 week-old male SGLT2 mutant (Sweet Pee) and wildtype (WT) mice, fed with normal or high fat diet (HFD, 60% calories from fat) for eight weeks, were analyzed. Weekly changes in body weight, food intake, insulin and glucose tolerance were determined. Renal injury was evaluated by transdermal measurement of GFR, urinary albumin creatinine ratio (uACR), KIM-1, NGAL and cleaved caspase 3 expression in the renal cortex and TUNEL staining of the kidney. Metabolic changes of the kidney were examined by qPCR of genes related to glycolysis, TCA cycle and fatty acid oxidation.

Results

Similar degree of HFD-induced obesity occurred in both SGLT2 mutant and WT mice while compensatory hyperphagia was observed only in mutant mice. HFD led to elevation of post-prandial blood glucose level, glucose intolerance and insulin resistance. Increases in postprandial blood glucose and glucose intolerance were blunted in SGLT2 mutant mice. Although changes of GFR and urinary albumin excretion were not observed, KIM1 and NGAL expression were upregulated by HFD feeding, indicating that this model represents an early phase of DKD. KIM1 and NGAL upregulation was abrogated in SGLT2 mutant mice. Furthermore, HFD feeding induced apoptosis in the cortex of WT mice, but not in SGLT2 mutants. Kidney/ body weight ratio was decreased by HFD in WT but increased in SGLT2 mutant mice, suggesting metabolic differences in the kidney. Genes related to glycolysis (PGK and PKM), TCA cycle (IDH2) and fatty acid oxidation (CPT1a, CPT2, PPARα and PGC1α) were suppressed in SGLT2 mutant vs WT HFD groups.

Conclusion

SGLT2 inhibition ameliorates tubular injury associated with renal hypertrophy and metabolic suppression in very early phase of diet-induced DKD.

Funding

  • NIDDK Support