Urahama Yoshimichi, Ohsaki Yuki, Fujita Yutaka, Maruyama Shoichi, Yuzawa Yukio, Matsuo Seiichi, Fujimoto Toyoshi
Division of Nephrology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan.
Am J Pathol. 2008 Nov;173(5):1286-94. doi: 10.2353/ajpath.2008.080137. Epub 2008 Oct 2.
Proteinuria is a major cause of tubulointerstitial kidney damage, and free fatty acids bound to albumin are thought to play an important role in its pathogenesis. However, the mechanism whereby proteinuria causes tubulointerstitial damage to the kidney is unclear. Using primary human renal proximal tubular cells, we observed that albumin replete with fatty acids (rBSA) and defatted albumin (dBSA) complexed with linoleic acid (LA) induced significantly more apoptosis than did defatted albumin alone. Oxidative stress was partially involved in apoptotic induction by LA/dBSA but not by rBSA. Administration of fatty acid-bound BSA increased the number of lipid droplets (LDs) and the LD-associated proteins, adipocyte differentiation-related protein and TIP47. LDs are organelles that store esterified fatty acids, and the LD-associated proteins are presumed to facilitate LD formation. Knockdown of adipocyte differentiation-related protein or TIP47 by RNA interference enhanced induction of apoptosis by both rBSA and LA/dBSA. Apoptotic induction was observed similarly when either rBSA or LA/dBSA was applied to only the apical surfaces of polarized LLC-PK1 cells. The present results suggest that LDs and LD-associated proteins have protective effects against apoptosis induced by fatty acid-bound albumin by sequestering free fatty acids. Therapeutic manipulation of these LD-associated proteins could aid in the amelioration of nephritic diseases.
蛋白尿是肾小管间质肾损伤的主要原因，与白蛋白结合的游离脂肪酸被认为在其发病机制中起重要作用。然而，蛋白尿导致肾脏肾小管间质损伤的机制尚不清楚。利用原代人肾近端小管细胞，我们观察到富含脂肪酸的白蛋白（rBSA）和与亚油酸（LA）复合的脱脂白蛋白（dBSA）比单独的脱脂白蛋白诱导的细胞凋亡明显更多。氧化应激部分参与了LA/dBSA诱导的凋亡，但不参与rBSA诱导的凋亡。给予脂肪酸结合的BSA增加了脂滴（LDs）的数量以及与LD相关的蛋白质、脂肪细胞分化相关蛋白和TIP47。LDs是储存酯化脂肪酸的细胞器，与LD相关的蛋白质被认为有助于LD的形成。通过RNA干扰敲低脂肪细胞分化相关蛋白或TIP47增强了rBSA和LA/dBSA诱导的细胞凋亡。当rBSA或LA/dBSA仅应用于极化的LLC-PK1细胞的顶端表面时，同样观察到细胞凋亡诱导。目前的结果表明，LDs和与LD相关的蛋白质通过隔离游离脂肪酸对脂肪酸结合白蛋白诱导的细胞凋亡具有保护作用。对这些与LD相关的蛋白质进行治疗性调控可能有助于改善肾病。
