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Originally published online as doi:10.2353/ajpath.2008.080137 on October 2, 2008

Published online before print October 2, 2008
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(American Journal of Pathology. 2008;173:1286-1294.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080137

Lipid Droplet-Associated Proteins Protect Renal Tubular Cells from Fatty Acid-Induced Apoptosis

Yoshimichi Urahama*{dagger}, Yuki Ohsaki{dagger}, Yutaka Fujita{dagger}, Shoichi Maruyama*, Yukio Yuzawa*, Seiichi Matsuo* and Toyoshi Fujimoto{dagger}

From the Department of Internal Medicine,* Division of Nephrology, and the Department of Anatomy and Molecular Cell Biology,{dagger} Nagoya University Graduate School of Medicine, Nagoya, Japan

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.






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