Muroya Yoshikazu, Ito Osamu
Department of General Medicine and Rehabilitation, Tohoku Medical and Pharmaceutical University School of Medicine, 1-12-1 Fukumuro, Miyagino-ku, Sendai, 983-8512, Japan.
Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
Clin Exp Nephrol. 2016 Dec;20(6):862-870. doi: 10.1007/s10157-016-1253-0. Epub 2016 Mar 7.
Proteinuria plays an essential role in the progression of tubulointerstitial damage, which causes end-stage renal disease. An increased load of fatty acids bound to albumin reabsorbed into proximal tubular epithelial cells (PTECs) contributes to tubulointerstitial damage. Fibrates, agonists of peroxisome proliferator-activated receptor α (PPARα), have renoprotective effects against proteinuria whereas the effects of these compounds on fatty acid metabolism in the kidney are still unknown. Therefore, the present study examined whether the renoprotective effects of clofibrate were associated with improvement of fatty acid metabolism in puromycin aminonucleoside (PAN)-induced nephrotic rats.
Rats were allocated to the control, PAN or clofibrate-treated PAN group. Biochemical parameters, renal injury and changes in fatty acid metabolism were studied on day14.
PAN increased proteinuria, lipid accumulation in PTECs, excretions of N-acetyl-β-D-glucosaminidase (NAG) and 8-hydroxydeoxyguanosine (8OHdG) and the area of caspase 3-positive tubular cells. It decreased renal expressions of medium-chain acyl-CoA dehydrogenase (MCAD), cytochrome P450 (CYP)4A, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα) without change of the expression of PPARα. Clofibrate reduced proteinuria, lipid accumulation, NAG excretion and the area of caspase 3-positive tubular cells. However, albumin excretion was not reduced and 8OHdG excretion was increased. Clofibrate minimized changes in MCAD, CYP4A, PGC-1α and ERRα expressions with increased PPARα, very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain acyl-CoA dehydrogenase (LCAD) expressions.
Clofibrate is protective against renal lipotoxicity in PAN nephrosis. This study indicates that clofibrate has renoprotective effects through maintaining fatty acid metabolism in the kidney of PAN-induced nephrotic rats.
蛋白尿在导致终末期肾病的肾小管间质损伤进展中起关键作用。重吸收进入近端肾小管上皮细胞（PTECs）的与白蛋白结合的脂肪酸负荷增加会导致肾小管间质损伤。贝特类药物是过氧化物酶体增殖物激活受体α（PPARα）的激动剂，对蛋白尿具有肾脏保护作用，而这些化合物对肾脏脂肪酸代谢的影响尚不清楚。因此，本研究探讨了氯贝丁酯的肾脏保护作用是否与改善嘌呤霉素氨基核苷（PAN）诱导的肾病大鼠的脂肪酸代谢有关。
将大鼠分为对照组、PAN组或氯贝丁酯治疗的PAN组。在第14天研究生化参数、肾损伤和脂肪酸代谢变化。
PAN增加了蛋白尿、PTECs中的脂质蓄积、N-乙酰-β-D-氨基葡萄糖苷酶（NAG）和8-羟基脱氧鸟苷（8OHdG）的排泄以及半胱天冬酶3阳性肾小管细胞的面积。它降低了中链酰基辅酶A脱氢酶（MCAD）、细胞色素P450（CYP）4A、过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）和雌激素相关受体α（ERRα）的肾脏表达，而PPARα的表达没有变化。氯贝丁酯减少了蛋白尿、脂质蓄积、NAG排泄和半胱天冬酶3阳性肾小管细胞的面积。然而，白蛋白排泄未减少，8OHdG排泄增加。氯贝丁酯使MCAD、CYP4A、PGC-1α和ERRα表达的变化最小化，同时PPARα、极长链酰基辅酶A脱氢酶（VLCAD）和长链酰基辅酶A脱氢酶（LCAD）的表达增加。
氯贝丁酯对PAN肾病中的肾脏脂毒性具有保护作用。本研究表明，氯贝丁酯通过维持PAN诱导的肾病大鼠肾脏中的脂肪酸代谢而具有肾脏保护作用。
