Multitarget molecule, PTUPB, to treat diabetic nephropathy in rats
Md Abdul Hye Khan1, Sung Hee Hwang2, Scott D Barnett1
1Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Background And Purpose:
Diabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase-2 inhibitor against diabetic nephropathy.
Experimental Approach:
Sixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8 weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) in the kidney of these and lean ZSF1 rats along with their blood pressure.
Key Result:
Obese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB-treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP-1 (CCR2) level and renal infiltration of CD-68 positive cells. PTUPB and enalapril significantly reduced urinary MCP-1 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.
Conclusion And Implications:
Overall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.
Insights
The dual modulator PTUPB effectively treats diabetic nephropathy, hypertension, and liver injury in type 2 diabetic rats, comparable to standard treatments, but does not lower blood glucose.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Diabetic nephropathy is a serious complication of type 2 diabetes, leading to high morbidity and mortality.
- Obese ZSF1 rats serve as a model for type 2 diabetes and diabetic nephropathy.
Purpose of the Study:
- To investigate the efficacy of PTUPB, a dual soluble epoxide hydrolase and cyclooxygenase-2 inhibitor, in treating diabetic nephropathy.
- To compare the effects of PTUPB with enalapril, a standard treatment, in a rat model.
Main Methods:
- Type 2 diabetic obese ZSF1 rats were treated with PTUPB, enalapril, or vehicle for 8 weeks.
- Measurements included blood glucose, HbA1c, kidney injury markers, inflammatory markers (MCP-1), blood pressure, and liver enzymes.
- Renal epoxyeicosatrienoic acids, thromboxane B2, and prostaglandin E2 levels were assessed.
Main Results:
- PTUPB and enalapril alleviated diabetic nephropathy and reduced blood pressure.
- PTUPB preserved glomerular nephrin expression and reduced renal inflammation markers.
- PTUPB also decreased hyperlipidemia and liver injury, while enalapril did not.
Conclusions:
- PTUPB effectively alleviates diabetic nephropathy, hypertension, hyperlipidemia, and liver injury in type 2 diabetic rats.
- Its renal protective effects are comparable to enalapril, a current standard treatment.
- PTUPB does not improve hyperglycemia but offers multi-organ benefits in this model.
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