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Abstract: FR-PO352

SGLT2 Inhibition Causes Methionine Metabolic Modulation in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Maekawa, Hiroshi, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Fain, Margaret E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Kaminski, Dorian, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Chandel, Navdeep S., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Therapeutic inhibition of the sodium glucose cotransporter 2 (SGLT2) protects the kidney although underlying mechanisms are incompletely known. We tested the hypothesis that cell-specific metabolic pathways activated by SGLT2 inhibition in diabetic kidney disease (DKD) underlie benefits.

Methods

Kidneys harvested from 10-week-old male Sglt2 mutant (MT) and wildtype (WT) mice, fed with normal or high fat diet (HFD, 60% calories from fat) for 8 or 18 weeks, were analyzed. Single cell RNA sequence (scRNA seq) analysis was performed on libraries prepared from whole kidneys. Metabolomic analysis of renal cortex was conducted by Metabolon, Inc. Two dosages (10 or 50 mg/kg BW) of Methionine Adenosyltransferase 2A inhibitor (MAT2Ai), an inhibitor of the methionine cycle, was injected into intraperitoneal cavity of WT/MT mice with prior exposure to HFD for 8 weeks. Human proximal tubular cells (HK-2), were exposed to 50 mM of D-glucose with/without 1uM of MAT2Ai or S-Adenosyl methionine (SAM) for 48hr.

Results

HFD-induced obesity was similar in both MT and WT while compensatory hyperphagia was observed in MT. Glucose intolerance occurred in mice fed HFD (WT>MT). Molecular and functional markers of kidney injury including serum creatinine, KIM-1, number of apoptotic cells and albuminuria were higher in WT>MT. Analysis of scRNA seq showed a new class of proximal tubular cells (New-PTC), predominantly found in HFD-fed WT. New-PTC showed increased expression of genes related to epithelial–mesenchymal transition (EMT), apoptosis and inflammation. Pathway enrichment analysis of metabolomic data uncovered differences in WT vs MT renal cortex; metabolites of methionine cycle including SAM were preferentially increased in HFD-fed MT. MAT2Ai abrogated renal protection with anti-inflammatory (reduced IL-6, IL-8, IL-1β and TNF) and fibrotic (reduced αSMA and SM22α) responses in MT. High glucose treatment of HK-2 recapitulated molecular changes observed in New-PTC, including markers of EMT (elevated fibronectin) and inflammation (increased IL-6, IL-8 and TNF) which could be inhibited by SAM supplementation, which enhances methionine metabolism. Conversely MAT2Ai exacerbated EMT and inflammation.

Conclusion

SGLT2 inhibition prevents the emergence of New-PTC with inflammatory and fibrotic phenotypes via methionine metabolic modulation in DKD.