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Kidney Week

Abstract: PO0684

Effect of Lisinopril and Pioglitazone in a Mouse Model of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hinke, Simon A., Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Cavanaugh, Cassandre, Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Nchaw, Gladys A., Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Chen, Tao, Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Stahle, Paul, Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Shukla, Neetu, Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Huang, Hui, Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Yang, Zhiyong, Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
  • Nawrocki, Andrea R., Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, Pennsylvania, United States
Background

Diabetic nephropathy affects up to one third of all diabetes mellitus patients, and is the major cause of end stage renal disease. The current study evaluated the uninephrectomized (UNx) obese and diabetic db/db mouse as a model of diabetic kidney disease (DKD), benchmarking a glycemic control agent (Pioglitazone) and an angiotensin-converting enzyme inhibitor (Lisinopril) to affect kidney structure and function.

Methods

Female lean control mice (Db/+, 2 kidneys), sham operated obese mice (db/db, 2 kidneys), and UNx db/db mice (1 kidney) were grouped based on body weight, blood glucose, %HbA1c, and urine albumin:creatinine ratio (UACR). Inclusion criteria were defined as blood glucose >350mg/dl and UACR >250ug/mg. Following grouping, animals were provided a diet admixture of Pioglitazone (169mg/Kg diet) or Lisinopril (0.1mg/mL) in drinking water. Compounds were administered for 8 weeks, during which body weight, food intake, water intake and blood glucose was measured.

Results

Control UNx-db/db animals showed progressive decline in renal function (UACR: 497±62mg/ug at baseline to 1054±159mg/ug at 8wks), whereas sham operated animals remained near baseline levels (284±40mg/ug). Pioglitazone treated mice had significantly lower UACR than control UNx-db/db after 2 weeks whereas lisinopril treated animals had significantly lower UACR after 4 weeks of treatment, primarily by limiting the progression of UACR increase. Increased mesangial matrix deposition in the glomeruli was the primary lesion observed (high incidence and high severity); tubular and interstitial structural findings were very limited; little to no fibrosis was observed. Pioglitazone and lisinopril both showed a comparable effect in decreasing the severity of mesangial matrix deposition.

Conclusion

Hence, the UNx-db/db animal model of diabetic kidney disease is a progressive model of renal function decline and limited histopathological damage which responds to both anti-diabetic and anti-hypertensive control agents, and is a valuable model for the assessment of new therapeutic targets for DKD.

Funding

  • Commercial Support