Lipid droplet-associated proteins protect renal tubular cells from fatty acid-induced apoptosis.
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.
Urahama
Yoshimichi
Y
Division of Nephrology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan. urahama@med.nagoya-u.ac.jp
Ohsaki
Yuki
Y
Fujita
Yutaka
Y
Maruyama
Shoichi
S
Yuzawa
Yukio
Y
Matsuo
Seiichi
S
Fujimoto
Toyoshi
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D050356:Lipid Metabolism / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D000070780:Perilipin-2; D000070796:Perilipin-3; D011257:Pregnancy Proteins / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013552:Swine; D033921:Vesicular Transport Proteins
D000975:Antioxidants; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C038196:PLIN3 protein, human; D000070780:Perilipin-2; D000070796:Perilipin-3; D011257:Pregnancy Proteins; D033921:Vesicular Transport Proteins; D012710:Serum Albumin, Bovine