Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa 125055, India.
Pharmacol Res. 2012 Oct;66(4):349-56. doi: 10.1016/j.phrs.2012.07.001. Epub 2012 Jul 14.
We have previously shown that the low-dose combination of fenofibrate and rosiglitazone might halt the progression of diabetes-induced nephropathy in rats. The present study investigated the combined effect of fenofibrate (PPARα agonist) and telmisartan (AT₁ receptor antagonist) in diabetes-induced onset of nephropathy in rats. The single administration of streptozotocin (STZ, 55 mg/kg i.p.) produced diabetes mellitus, which subsequently produced nephropathy in 8 weeks by markedly elevating serum creatinine, blood urea nitrogen and microproteinuria. In addition, histopathological studies revealed the development of renal structural abnormalities such as mesangial expansion, glomerular and tubular damage. Moreover, diabetes-induced nephropathy was accompanied with high renal oxidative stress and lipid alteration. Treatment with fenofibrate (80 mg/kg/day, p.o., 4 weeks) and telmisartan (10 mg/kg/day, p.o., 4 weeks) either alone or in combination did not affect the elevated glucose levels in diabetic rats. Albeit treatment with fenofibrate normalizes the altered lipid profile in diabetic rats, telmisartan treatment has no effect on it. Treatment with fenofibrate and telmisartan either alone or in combination markedly prevented diabetes-induced onset of nephropathy and renal oxidative stress. Their combination was as good as to their individual treatment, but not superior in attenuating the diabetes-induced nephropathy and renal oxidative stress. It may be concluded that diabetes-induced oxidative stress and lipid alteration, besides hyperglycemia, could play a key role in the induction of nephropathy. Fenofibrate and telmisartan individual treatment was equipotent in preventing the onset of diabetes-induced experimental nephropathy, while their combination did not afford additional benefits in preventing the disease induction of the diabetic kidney.
我们之前已经表明，非诺贝特和罗格列酮的低剂量联合可能会阻止糖尿病引起的大鼠肾病进展。本研究探讨了非诺贝特（PPARα 激动剂）和替米沙坦（AT₁ 受体拮抗剂）联合治疗糖尿病诱导的大鼠肾病发病的效果。单次给予链脲佐菌素（STZ，55mg/kg 腹腔注射）可产生糖尿病，随后在 8 周内通过显著升高血清肌酐、血尿素氮和微量蛋白尿引起肾病。此外，组织病理学研究显示出肾脏结构异常的发展，如系膜扩张、肾小球和肾小管损伤。此外，糖尿病诱导的肾病伴有肾氧化应激和脂质改变增加。单独或联合使用非诺贝特（80mg/kg/天，口服，4 周）和替米沙坦（10mg/kg/天，口服，4 周）治疗不会影响糖尿病大鼠升高的血糖水平。虽然非诺贝特治疗可使糖尿病大鼠改变的脂质谱正常化，但替米沙坦治疗对此无影响。单独或联合使用非诺贝特和替米沙坦可显著预防糖尿病诱导的肾病发病和肾氧化应激。它们的联合治疗与单独治疗一样有效，但在减轻糖尿病诱导的肾病和肾氧化应激方面没有优势。可以得出结论，除高血糖外，糖尿病诱导的氧化应激和脂质改变可能在诱导肾病中起关键作用。非诺贝特和替米沙坦单独治疗在预防糖尿病诱导的实验性肾病发病方面具有同等效力，而它们的联合治疗在预防糖尿病肾脏疾病的发病方面没有额外益处。
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