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Abstract: FR-PO182

SGLT2 Inhibition Promotes Restoration of Podocyte Number and Regression of Diabetic Nephropathy in BTBR ob/ob Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hudkins, Kelly L., University of Washington, Seattle, Washington, United States
  • Li, Xianwu, University of Washington, Seattle, Washington, United States
  • Holland, Alexander Lucas, University of Washington, Seattle, Washington, United States
  • Alpers, Charles E., University of Washington, Seattle, Washington, United States

Group or Team Name

  • Alpers Lab
Background

The SGLT2 inhibitor empagliflozin (EMPA) lowers blood glucose in diabetic patients via enhanced urinary excretion of glucose and ameliorates complications of type II diabetes, including cardiovascular disease and nephropathy (DN) through additional mechanisms, not fully defined.

Methods

: Cohorts of 18 week old BTBR ob/ob and BTBR WT littermates (n=12) were fed chow formulated with 300 mg/kg EMPA with and without concurrent losartan (LOS) treatment, normal chow or were given leptin (LEP) for 6 weeks.

Results

Treatment with LEP, EMPA and EMPA+LOS but not LOS alone all resulted in significant reductions of blood glucose and HbA1c. BTBR ob/ob mice have elevated albumin creatinine ratio (ACR) (737 ug/mg); treatment with LEP, EMPA, LOS and EMPA+LOS all reduced ACR (88, 224, 162 and 112 ug/mg respectively, p<0.01). Morphologic analysis of silver stained tissue sections demonstrated significant reductions in mesangial matrix accumulation as percentage of glomerulus (G) tuft area in all treatment groups except LOS (ob/ob 20.8%, LEP 13.3%, EMPA 14%, and EMPA+LOS 12.5%, p<0.01; LOS 18.4%, ns). Podocyte density increased with EMPA treatment vs. untreated ob/ob (ob/ob 89.2, LEP 124, p<0.05; EMPA 145.3, p<0.001; EMPA+LOS 171.1 podos/x106 um3, p<0.001). EMPA treatment decreased Mac2+ macrophages within glomeruli (ob/ob 1.85, EMPA 0.95 Mac2+ cells/G, p <0.01), but EMPA+LOS had numbers of glomerular macrophages similar to the untreated ob/ob mice (1.64 Mac2+ cells/G, ns). In contrast, qPCR for 3 inflammatory cytokines, MCP-1, IL-6 and TNFa were unchanged with EMPA, but significantly decreased with LOS and EMPA+LOS (p<0.05). In the interstitium, F4/80+ macrophages were decreased only with LEP treatment. Oxidative stress, measured by urinary 8OHdG/Cre and in tissue sections by cellular localization of nonspecific protein oxidation was decreased in all groups.

Conclusion

EMPA and EMPA+LOS treatment is similar to leptin replacement in ameliorating many of the pathologic and clinical manifestations of DN in the leptin deficient BTBR ob/ob mouse. Podocyte density was restored, oxidative stress and proteinuria decreased with SGLT2 inhibition. These may all be contributing factors in the improvement seen in human diabetic patients treated with SGLT2 inhibitors.

Funding

  • Commercial Support