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OBJECTIVE--Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis, and inflammation. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland, and kidney. The primary bile acids are the highest affinity endogenous ligands for FXR. The effects of FXR agonists in diabetic kidney disease, the main cause of end-stage renal disease, however, have not been determined. RESEARCH DESIGN AND METHODS--To identify the effect of FXR activation in modulation of diabetic nephropathy, we treated 1) C57BL/6J mice on low-fat diet or high-fat diet with FXR agonists (GW4064 or cholic acid) for 1 week; 2) C57BLKS/J-db/db mice and their lean mates with GW4064 for 1 week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks. RESULTS--We found that FXR agonists modulate renal sterol regulatory element-binding protein-1 (SREBP-1) expression and lipid metabolism and renal expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress enzymes and decrease glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. In renal mesangial cells, overexpression of FXR or treatment with GW4064 also inhibited SREBP-1c and other lipogenic genes, transforming growth factor-β, and interleukin-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation. CONCLUSIONS--These results therefore indicate a new and important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy. Diabetes 56:2485-2493, 2007 [ABSTRACT FROM AUTHOR]

Diabetic kidney disease has been associated with the presence of lipid deposits, but the mechanisms for the lipid accumulation have not been fully determined. In the present study, we found that db/db mice on the FVB genetic background with loss-of-function mutation of the leptin receptor (FVB-Leprdb mice or FVBdb/db) develop severe diabetic nephropathy, including glomerulosclerosis, tubulointerstitial fibrosis, increased expression of type IV collagen and fibronectin, and proteinuria, which is associated with increased renal mRNA abundance of transforming growth factor-β, plasminogen activator inhibitor-1, and vascular endothelial growth factor. Electron microscopy demonstrates increases in glomerular basement membrane thickness and foot process (podocyte) length. We found that there is a marked increase in neutral lipid deposits in glomeruli and tubules by oil red O staining and biochemical analysis for cholesterol and triglycerides. We also detected a significant increase in the renal expression of adipocyte differentiation-related protein (adipophilin), a marker of cytoplasmic lipid droplets. We examined the expression of sterol regulatory element-binding protein (SREBP)-1 and -2, transcriptional factors that play an important role in the regulation of fatty acid, triglyceride, and cholesterol synthesis. We found significant increases in SREBP-1 and -2 protein levels in nuclear extracts from the kidneys of FVBdb/db mice, with increases in the mRNA abundance of acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase, which mediates the increase in renal triglyceride and cholesterol content. Our results indicate that in FVBdb/db mice, renal triglyceride and cholesterol accumulation is mediated by increased activity of SREBP-1 and -2. Based on our previous results with transgenic mice overexpressing SREBP-1 in the kidney, we propose that increased expression of SREBPs plays an important role in causing renal lipid accumulation, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria in mice with type 2 diabetes. Diabetes 54:2328-2335, 2005 [ABSTRACT FROM AUTHOR]

There is a strong concordance in renal and cardiovascular disease in T2DM. Abnormalities in lipid metabolism could be the link between these conditions. Kidney lipid content has been associated with renal injury in DM rodents, but has not been studied in higher species. Sterol regulatory element binding proteins (SERBPs), important regulators of lipid and carbohydrate metabolism, inflammation and fibrosis, and stearoyl-CoA desaturase 1 (SCD1), an SREBP-1 target enzyme critical for triglyceride (TG) synthesis and esterification of free cholesterol (Chol), are highly expressed in the kidney. Spontaneously obese and T2DM rhesus monkeys have glomerular lesions very closely resembling those of human T2DM. We evaluated whether relationships between renal structure and renal lipid content and metabolism were present in this excellent T2DM diabetic nephropathy (DN) model. We studied 7 T2DM, 5 PreDM, and 3 age-matched normal (N) rhesus monkeys that had renal tissues obtained at euthanasia for light microscopy (LM) and lipid studies. Index of mesangial expansion (IME), a semi-quantitative estimate performed on PAS LM slides, is strongly correlated with electron microscopy measured mesangial fractional volume (r=0.86; p<0.0005). Lipid content and SREBP-I, SREBP-2, and SCD1 protein levels were determined on renal cortical tissues. IME and % of sclerosed glomeruli (SG) and tuft to Bowman's capsule adhesions (TBCA) were higher (p<0.05) and % of focal segmental glomerulosclerosis (FSGS) not different in DM vs. N or PreDM monkeys (Table). SREBP- 1 and SREBP-2 were increased in kidneys of DM vs. N monkeys (p<0.05). Renal cortical Chol tended to correlate with %SG (r=0.62; p=0.058). SREBP-1 correlated with IME (r=0.70; p<0.05) and TBCA (r=0.68; p<0.05). SCD-1 also correlated with IME (r=0.65; p<0.01) and TBCA (r=0.58; p=0.023). These are the first direct studies in primates linking lipid metabolism to DN. These "proof of concept" results encourage further studies in this model and in humans, which may uncover the missing linkage between macrovascular and kidney disease in T2DM. [ABSTRACT FROM AUTHOR]