Katary Mohamed M, Pye Chelsey, Elmarakby Ahmed A
Department of Oral Biology & Pharmacology, Augusta University, Augusta, GA, United States; Department of Pharmacology, Faculty of Pharmacy, Damanhur University, Egypt.
Department of Oral Biology & Pharmacology, Augusta University, Augusta, GA, United States.
Prostaglandins Other Lipid Mediat. 2017 Sep;132:3-11. doi: 10.1016/j.prostaglandins.2016.08.004. Epub 2016 Sep 3.
The pro-inflammatory cyclooxygenase (COX)-derived prostaglandins and the anti-inflammatory cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) play an important role in the regulation of renal injury. The current study examined whether COX inhibition augments the reno-protective effects of increased EETs levels via inhibiting EETs degradation by soluble epoxide hydrolase (sEH) in diabetic rats. Streptozotocin (50mg/kg, i.v) was used to induce diabetes in male Sprague Dawley rats. Rats were then divided into 5 groups (n=6-8); control non diabetic, diabetic, diabetic treated with the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), diabetic treated with the COX inhibitor meloxicam and diabetic treated with meloxicam plus t-AUCB for 2 months. Glomerular albumin permeability and urinary albumin and nephrin excretion levels were significantly elevated in diabetic rats together with decreased glomerular α3 integrin and nephrin expression levels. Inhibition of sEH reduced glomerular albumin permeability, albumin and nephrin excretion levels and restored the decrease in glomerular α3 integrin and nephrin expression in diabetic rats. Meloxicam failed to reduce renal injury or even to synergize the reno-protective effects of sEH inhibition in diabetic rats. Furthermore, inhibition of sEH reduced the elevation in renal collagen deposition and urinary MCP-1 excretion levels together with a reduction in the number of renal TUNEL positive cells in diabetic vs. control rats (P<0.05). Meloxicam did not reduce renal inflammation or apoptosis in diabetic rats or even exacerbate the anti-inflammatory and anti-apoptotic effects of sEH inhibition. Renal 20-hydroxyeicosatetranoic acid (20-HETE) levels were elevated in diabetic rats and meloxicam further exacerbated this elevation. In conclusion, our study suggests that inhibition of COX failed to provide renal protection or to augment the reno-protective effects of sEH inhibition in diabetic rats, at least in part, via increased inflammatory 20-HETE levels.
促炎环氧化酶（COX）衍生的前列腺素和抗炎细胞色素P450环氧合酶衍生的环氧二十碳三烯酸（EETs）在肾损伤调节中起重要作用。本研究检测了在糖尿病大鼠中，COX抑制是否通过抑制可溶性环氧化物水解酶（sEH）对EETs的降解来增强升高的EETs水平的肾保护作用。用链脲佐菌素（50mg/kg，静脉注射）诱导雄性Sprague Dawley大鼠患糖尿病。然后将大鼠分为5组（n = 6 - 8）；对照非糖尿病组、糖尿病组、用sEH抑制剂反式-4-[4-(3-金刚烷-1-基-脲基)-环己氧基]-苯甲酸（t-AUCB）治疗的糖尿病组、用COX抑制剂美洛昔康治疗的糖尿病组以及用美洛昔康加t-AUCB治疗2个月的糖尿病组。糖尿病大鼠的肾小球白蛋白通透性、尿白蛋白和nephrin排泄水平显著升高，同时肾小球α3整合素和nephrin表达水平降低。抑制sEH可降低糖尿病大鼠的肾小球白蛋白通透性、白蛋白和nephrin排泄水平，并恢复肾小球α3整合素和nephrin表达的降低。美洛昔康未能减轻肾损伤，甚至未能协同sEH抑制在糖尿病大鼠中的肾保护作用。此外，抑制sEH可降低糖尿病大鼠与对照大鼠相比肾胶原沉积的升高和尿MCP-1排泄水平，同时减少肾TUNEL阳性细胞数量（P<0.05）。美洛昔康未减轻糖尿病大鼠的肾炎症或凋亡，甚至加剧了sEH抑制的抗炎和抗凋亡作用。糖尿病大鼠肾20-羟基二十碳四烯酸（20-HETE）水平升高，美洛昔康进一步加剧了这种升高。总之，我们的研究表明，抑制COX未能提供肾保护，或至少部分通过增加炎性20-HETE水平来增强sEH抑制在糖尿病大鼠中的肾保护作用。
