title: SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells.
abstract: Free fatty acid (FFA)-mediated renal lipotoxicity is associated with the progression of tubulointerstitial inflammation in proteinuric kidney disease. SIRT3 is an antiaging molecule regulated by calorie restriction and mitochondria-localized NAD(+)-dependent deacetylase. In this study, we investigated whether SIRT3 reversed renal lipotoxicity-mediated ROS and inflammation. In the kidney of the FFA-bound BSA-overloaded mouse, which is a well-established experimental model of FFA-associated tubulointerstitial inflammation, mRNA expression of SIRT3 was significantly decreased and negatively correlated with mRNA expression of an inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). In cultured proximal tubular (mProx) cells, the saturated FFA palmitate stimulated ROS accumulation and expression of MCP-1. These effects were ameliorated by retrovirus-mediated overexpression of SIRT3, whereas they were exacerbated by either overexpression of a dominant-negative form of SIRT3(N87A) lacking deacetylase activity or knockdown of SIRT3 by siRNA transfection. Furthermore, we showed that SIRT3 positively regulated both mitochondrial oxidative capacity and antioxidant gene expression, thereby reducing ROS accumulation in mProx cells, which suggests a mechanism that underlies SIRT3-mediated reversal of palmitate-induced inflammation. In conclusion, these results highlight a new role for SIRT3 in lipotoxicity/ROS-related inflammation, reveal a new molecular mechanism underlying calorie restriction-mediated antioxidant and anti-inflammatory effects, and could aid in the design of new therapies for the prevention of tubulointerstitial lesions in proteinuric kidney disease.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Koyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Keiji
authors.initials: K
authors.lastname: Isshiki
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007249:Inflammation; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009395:Nephritis, Interstitial / Q000178:diet therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D010168:Palmitates / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D010168:Palmitates; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3