Dual sEH/COX-2 Inhibition Using PTUPB—A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity

Abstract

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. The drug was administered to male Sprague–Dawley rats that were on a high-salt diet. Sorafenib was administered over the course of 56 days. The study included three experimental groups; 1) control group (naïve rats), 2) sorafenib group [rats treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group (rats treated with sorafenib only for the initial 28 days and subsequently coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure was measured every 2 weeks. After 28 days, sorafenib-treated rats developed hypertension (161 ± 4 mmHg). Over the remainder of the study, sorafenib treatment resulted in a further elevation in blood pressure through day 56 (200 ± 7 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by day 56, blood pressure was 159 ± 4 mmHg. Urine was collected every 2 weeks for biochemical analysis. After 28 days, sorafenib rats developed pronounced proteinuria (9.7 ± 0.2 P/C), which intensified significantly (35.8 ± 3.5 P/C) by the end of day 56 compared with control (2.6 ± 0.4 P/C). PTUPB mitigated sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. Plasma and kidney tissues were collected on day 56. Kidney histopathology revealed intratubular cast formation, interstitial fibrosis, glomerular injury, and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment reduced histological features by 30%–70% compared with the sorafenib-treated group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on the glomerular permeability barrier by decreasing angiotensin-II-induced glomerular permeability to albumin. Finally, PTUPB improved in vitro the viability of human mesangial cells. Collectively, our data demonstrate the potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

“…Beyond AChE, we think it would be of great interest to combine sEH with other targets with a role in inflammation mediated by arachidonic acid metabolites, such as COX2 and LOX5, and with PPARγ receptors, which are expressed in neurons, where they are involved in inflammation, oxidative stress, and neuronal death [ 78 ]. On the one hand, a few examples of dual inhibitors of sEH/COX2 [ 79 ], sEH/LOX5 [ 80 ], and dual sEH inhibitors/PPARγ activators [ 81 ] have been developed for non-neurological applications, in which the multitarget compounds displayed positive effects against inflammation and oxidative stress. On the other hand, COX2 and LOX5 have been already used, albeit only very marginally, and PPARγ receptor has been suggested to be used in the design of multitarget anti-AD agents, but not in combination with sEH.…”

Regulation of soluble epoxide hydrolase in renal-associated diseases: insights from potential mechanisms to clinical researches

“…PTUPB effectively reduces sorafenib-induced glomerular nephrotoxicity. PTUPB can lower blood pressure and proteinuria, alleviate tubular and fibrotic damage, and improve glomerular health ( 72 ). These data suggest that inhibiting sEH can alleviate chemotherapeutic agent-induced kidney injury.…”

“…Besides, CYP450-derived EETs, especially 8,9-EETs, can be further metabolized by COX enzymes to angiogenic 11-hydroxy-8,9-EETs ( 89 , 90 ). The single molecule sEH/COX-2 dual inhibitor, PTUPB, can lower blood pressure and proteinuria, alleviate tubular and fibrotic damage, and improve glomerular health ( 72 ). In type 2 diabetic obese ZSF1 rats, PTUPB reduced renal cytokine expression, decreased immune cell infiltration, and reduced production of chemokine MCP-1 to alleviate kidney inflammation.…”