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MULTI-TARGET MOLECULE TO TREAT DIABETIC NEPHROPATHY IN RATS
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  • Md Abdul Khan,
  • Sung Hee Hwang,
  • Scott Barnett,
  • Anna Burkhan,
  • Wojciech Jankiewicz,
  • Bruce Hammock,
  • John Imig
Md Abdul Khan
Medical College of Wisconsin
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Sung Hee Hwang
University of California
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Scott Barnett
Medical College of Wisconsin
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Anna Burkhan
Medical College of Wisconsin
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Wojciech Jankiewicz
Medical College of Wisconsin
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Bruce Hammock
University of California
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John Imig
Medical College of Wisconsin
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Abstract

Background and Purpose: Diabetic nephropathy is one of the most common complications that is related to high morbidity and mortality in type 2 diabetic patients. We investigated ability of a novel dual modulator, PTUPB that concurrently acts as a soluble epoxide hydrolase inhibitor and as a cyclooxygenase-2 inhibitor against diabetic nephropathy. Experimental Approach: Sixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were orally treated with vehicle, PTUPB, or enalapril for 8 weeks. Key Results: PTUPB alleviated diabetic nephropathy in obese ZSF1 rats by reducing albuminuria by 50%, renal tubular cast formation by 60-70%, renal fibrosis by 40-50%, glomerular injury by 55% and preserved glomerular nephrin expression. Enalapril demonstrated comparable effects and alleviated diabetic nephropathy in obese ZSF1 rats by reducing all kidney injury parameters by 30 to 50%. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with 6-7-fold higher urinary MCP-1 level and renal infiltration of CD-68 positive cells. PTUPB and enalapril reduced renal inflammation but PTUPB demonstrated superior anti-inflammatory actions than enalapril. Obese ZSF1 rats were also hypertensive, hyperlipidemic, and exhibited liver injury. Interestingly, PTUPB but not enalapril decreased hyperlipidemia and liver injury in Obese ZSF1 rats. Conclusion and Implication: Overall, we demonstrate that a dual modulator PTUPB does not treat hyperglycemia, but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidemia, and liver injury in type 2 diabetic rats. Therefore, we suggest that PTUPB has promising potential to be developed as a novel therapy for type 2 diabetic nephropathy and other complications.

Peer review status:UNDER REVIEW

11 Sep 2020Submitted to British Journal of Pharmacology
12 Sep 2020Assigned to Editor
12 Sep 2020Submission Checks Completed
14 Sep 2020Reviewer(s) Assigned