We previously reported that a single nucleotide polymorphism (SNP), rs2268338, within the gene encoding ACCβ was associated with susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes. Although subsequent functional analyses suggested that increased expression of ACCβ in the kidney contributed to susceptibility to the disease, its pathological significance has not been fully elucidated yet. Methods: To know the role of ACCβ in the pathogenesis of diabetic

nephropathy, we examined the effect of ACCβ overexpression on podocyte injury using podocyte-specific ACCβ transgenic (TG) mice and ACCβ-overexpressing cultured murine podocytes. Results: TG mice showed normal renal manifestation under non-diabetic condition. However, 12 weeks after induction of diabetes Dorsomorphin nmr by streptozotocin injection, the increase of urinary albumin excretion was exacerbated in TG mice, RG7420 accompanied by a decrease in the expression of synaptopodin in podocytes,

compared to wild-type mice. In cultured murine podocytes infected with adenovirus vectors encoding ACCβ, the expression of synaptopodin and podocin decreased under high glucose condition, but not under normal glucose condition. Furthermore, overexpression of ACCβ under high glucose condition resulted in reorganization of stress fibers, increased production of cytokines such as MCP-1, IL-6, TNF-α and VEGF, and induction of apoptosis in the murine podocytes. AMP-activated protein kinase (AMPK) is the main kinase regulator of ACCβ, which inactivates ACCβ through the phosphorylation

of serine residues on ACCβ. The AMPK activation by 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) ameliorated ACCβ-induced decrease in the expression of synaptopodin and podocin, reorganization of stress fibers, increased production of cytokines, and induction of apoptosis under high glucose condition in the murine podocytes. Conclusion: From these observations, it is suggested that excess of ACCβ contributes to exacerbation of podocyte injury in diabetic nephropathy, and the regulation of AMPK/ACCβ pathway may be a new therapeutic strategy to prevent podocyte injury in patients with diabetic nephropathy. JHA JAY C1,2, GRAY STEPHEN P1, WINGLER KIRSTIN3, SZYNDRALEWIEZ Farnesyltransferase CEDRIC4, HEITZ FREDDY4, COOPER MARK E1,2, SCHMIDT HARALD HHW3, JANDELEIT-DAHM KARIN A1,2 1Diabetic complications division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; 2Department of medicine, Monash university, Melbourne, Australia; 3Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Netherlands; 4Genkyotex SA, Geneva, Switzerland Introduction: Chronic kidney disease is a major complication of diabetes. However, the underlying causes remain unclear.