No abstract

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

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 B 2 (TBX 2 ) and prostaglandin E2 (PGE 2 ) in the kidney of these and lean ZSF1 rats along with their blood pressure.

Kidney fibrosis is a key event in the development of chronic kidney disease, leading to end-stage renal failure. Unfortunately, there are now few drugs capable of preventing fibrosis in the kidneys, which is accompanied by the progression of chronic kidney disease in the terminal stage of renal failure. The results show the effectiveness of the use of a new dual-acting agent DM509 in the prevention of renal fibrosis using a model of unilateral obstruction of the ureter in mice. DM509 is both a farnesoid X-receptor agonist and a soluble epoxyhydrolase inhibitor. In this study, there were 8-12 week old C57BL/6J males undergoing surgery, which led to the development of unilateral ureteral obstruction and a control group. Mice received DM509 (10 mg/kg/day) or DM509-free solution together with drinking water for 10 days the day before surgery. Samples of kidney and blood tissues were collected at the end of the experiment. In the unilateral ureteral obstruction group, kidney dysfunction was detected, which was accompanied by increased urea nitrogen content in the blood compared to the control group (63 ± 7 vs. 34 ± 6 mg/d). The reduction of urea nitrogen in the blood by 36 % in mice with unilateral ureteral obstruction treated with DM509 is shown compared to mice with this pathology without treatment, which in turn proved the effectiveness of DM509 in preventing renal dysfunction. In mice with unilateral ureteral obstruction, which did not receive DM509, the development of kidney fibrosis with a high content of hydroxyproline in the kidneys and also increased collagen content in histological sections of the kidneys were detected. In the DM509 group, the renal and collagen hydroxyproline content was 34-66 % lower, indicating the effectiveness of this agent in the treatment of renal fibrosis. Thus, we have shown that the new DM509 is effective in preventing renal dysfunction and renal fibrosis using a murine model of unilateral ureteral obstruction.

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. What is already known?Diabetic nephropathy is the leading cause of death and disability in type 2 diabetic patients. Complex pathophysiology of diabetic nephropathy makes it difficult to treat and often requires multiple treatment approaches. What this study adds?We demonstrate strong pre-clinical therapeutic efficacy of a novel bifunctional molecule to treat diabetic nephropathy and other diabetic complications. What is the clinical significance?The multi-target drug PTUPB has compelling potential to treat type 2 diabetic complications.