Multitarget molecule, PTUPB, to treat diabetic nephropathy in rats

Khan, M. Mahmud; Hwang, Sung Hee; Barnett, Scott D.; Stavniichuk, Anna; Jankiewicz, Wojciech K.; Hammock, Bruce D.; Imig, John D.

doi:10.1111/bph.15623

Cited by 7 publications

(12 citation statements)

References 90 publications

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“…Indeed, combined sEH and COX-2 inhibition with PTUPB decreased sorafenib-induced nephrotoxicity. Our present finding is consistent with the previous studies using Zucker diabetic rats, where PTUPB was also found to decrease kidney injury and proteinuria ( Hye Khan et al, 2016 ; Khan et al, 2021 ).…”

Section: Discussionsupporting

confidence: 94%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 94%

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

et al. 2021

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“…33 PTUPB also decreased inflammation and fibrosis in the kidney and liver of obese ZSF-1 hypertensive and diabetic rats. 33 PTUPB treatment exhibited anti-inflammatory and anti-fibrotic actions in animal models of sepsis, non-alcoholic liver disease (NAFLD), and pulmonary fibrosis. 36,37,38,39 Taken together, these studies demonstrate the potential for PTUPB to decrease inflammation and oxidative stress and combat fibrosis to slow the progression of diabetic kidney injury.…”

Section: Ptupbmentioning

confidence: 80%

“…19,31,32 The ability for PTUPB to increase EETs and lower COX-2 metabolites without significantly altering other arachidonic acid metabolites has been demonstrated in multiple studies. 33,34,35 These studies have not extensively evaluated the effects of PTUPB on mRNA or protein expression of lipoxygenase, CYP4A, or CYP2C enzymes. The effects of PTUPB on glucose homeostasis and kidney injury were first evaluated in ZDF rats treated in a preventive manner for two months.…”

Section: Ptupbmentioning

confidence: 99%

“…As for systemic actions, multi-target drugs have been designed in many cases to have beneficial effects on systemic disease in addition to combating kidney diseases (Figure 3). 33,46,52,54 A strategy to limit systemic drug side effects when direct kidney actions are desired is to use kidney targeting strategies. 66,67 Kidney targeting with folate conjugation has been successful demonstrated with EET analogs.…”

Section: Other Potential Multi-target Drugs For Kidney Diseasesmentioning

confidence: 99%

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Multi-Target Drugs for Kidney Diseases

2021

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Kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), and glomerular nephritis can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell-signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past ten years, in silico design of drugs has allowed for multi-target drugs to go quickly from concept to reality. Several multi-target drugs have been successfully made that target arachidonic acid pathways and transcription factors to treat inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal transforming growth factor-β (TGF-β) signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.

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“…Pharmacological manipulation of sEH by t-AUCB in db/db mice significantly attenuated diabetic renal injury through reliving mitochondrial dysfunction and ER stress via inhibition of inflammation and autophagy [109]. A COX-2/sEH dual inhibitor PTUPB also significantly reduced urinary MCP-1 levels and renal cytokine expression, and therefore alleviated the development of diabetic nephropathy in rat [110]. In context of diabetic retinopathy, expression of CYP2B2 was significantly downregulated and 11,12-EET promoted angiogenesis in the retina under ischemia and hypoxia caused by diabetes [111,112] (Figure 4).…”

Section: Eets and Diabetic Complicationmentioning

confidence: 97%

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators

Shi¹,

Wang

2022

Molecules

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Inflammation plays a crucial role in the initiation and development of a wide range of systemic illnesses. Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid (AA) metabolized by CYP450 epoxygenase (CYP450) and are subsequently hydrolyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs), which are merely biologically active. EETs possess a wide range of established protective effects on many systems of which anti-inflammatory actions have gained great interest. EETs attenuate vascular inflammation and remodeling by inhibiting activation of endothelial cells and reducing cross-talk between inflammatory cells and blood vessels. EETs also process direct and indirect anti-inflammatory properties in the myocardium and therefore alleviate inflammatory cardiomyopathy and cardiac remodeling. Moreover, emerging studies show the substantial roles of EETs in relieving inflammation under other pathophysiological environments, such as diabetes, sepsis, lung injuries, neurodegenerative disease, hepatic diseases, kidney injury, and arthritis. Furthermore, pharmacological manipulations of the AA-CYP450-EETs-sEH pathway have demonstrated a contribution to the alleviation of numerous inflammatory diseases, which highlight a therapeutic potential of drugs targeting this pathway. This review summarizes the progress of AA-CYP450-EETs-sEH pathway in regulation of inflammation under different pathological conditions and discusses the existing challenges and future direction of this research field.

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Multitarget molecule, PTUPB, to treat diabetic nephropathy in rats

Cited by 7 publications

References 90 publications

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

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

Multi-Target Drugs for Kidney Diseases

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators

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