t0901317 and Diabetic-Nephropathies

Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death.

Topics: Benzoates; Benzylamines; Carnitine O-Palmitoyltransferase; Cell Death; Cells, Cultured; Diabetic Nephropathies; Fatty Acids, Monounsaturated; Gene Expression Regulation; Gene Knockdown Techniques; Gene Silencing; Humans; Hydrocarbons, Fluorinated; Kidney Glomerulus; Models, Biological; Oxidation-Reduction; Palmitic Acid; Podocytes; Protective Agents; Stearoyl-CoA Desaturase; Sulfonamides; Triglycerides

Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Gene Expression; Hydrocarbons, Fluorinated; Inflammation Mediators; Kidney; Ligands; Liver X Receptors; Macrophages; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Osteopontin; Promoter Regions, Genetic; RNA, Messenger; Sulfonamides; Transcription Factor AP-1