Abstract: SA-PO122

Linagliptin Treatment versus RAAS Inhibition Alone Improves Murine Diabetic Nephropathy

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Batorsky, Anna, University of Washington, Seattle, Washington, United States
  • Sanchez avila, Monica, University of Washington, Seattle, Washington, United States
  • Hudkins, Kelly L., University of WA, Seattle, Washington, United States
  • Alpers, Charles E., University of Washington Medical Center, Seattle, Washington, United States
Background

Linagliptin (LIN) and other DPP4 inhibitors have proven effects as treatments for diabetes (DM), but the renal benefit is not well understood. We explore effects of LIN, and LIN in combination with the ARB, losartan (LOS), on diabetic nephropathy (DN). The leptin-deficient BTBR ob/ob (OB) mouse is shown to mimic morphologically advanced human DN and type II DM. Administration of leptin (LEP) is shown to reduce body weight by 20-40%, return mice to normoglycemic levels, and improve functional and structural characteristics of DN.

Methods

Cohorts of female mice (n=12) were treated with LIN (83mg/kg in chow), LOS (100mg/mL in drinking water), combined LIN/LOS or LEP for 6 weeks starting at 18 weeks of age. We collected 6-hour fasting glucose and protein excretion measurements for all mice at 18 and 24 weeks. Baseline structural characteristics for WT and OB mice were determined by sacrificing untreated mice at 18 weeks. Glomerular abnormalities assessed at 24 weeks include expansion of silver stained mesangial matrix by computer morphometry, and podocyte density using the p57 marker of mature podocytes. Renal function was assessed by measurement of urine albumin/creatinine ratio (UACR) and measurement of 8-OHdG in urine as a marker of DNA/RNA damage.

Results

LIN-treated mice exhibit reduced mesangial expansion (13.6% silver positive matrix per glomerular cross section) compared to untreated mice (18.4%) at 24 weeks (p=0.02). Treatment with LOS, or LIN/LOS resulted in statistically significant reduction in UACR when paired 18 and 24 week urine samples were analyzed (p=0.032, 0.035 respectively). An ELISA assay for 8-OHdG in urine showed all treatment groups have significantly lower levels of oxidative damage compared to untreated controls at 24 weeks (WT 28.2, 24wk OB 93.1, 24wk OB LIN 35.4, 24wk OB LIN/LOS 30.5, 24wk OB LOS 41.4, 24wk OB LEP 39.6 ng 8-OHdG/mg Cre, p<0.001). LEP-treated mice had restored podocyte density, but no significant difference was detected between other treatment groups and untreated controls.

Conclusion

Our results suggest that DPP4- and RAAS-inhibition may ameliorate features of DN via mechanisms independent of restored podocyte density.

Funding

  • Commercial Support