Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory elementbinding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c ؊/؊ mice. In contrast to control mice, in the SREBP-1c ؊/؊ mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway.Obesity is a known risk factor for cardiovascular disease (1) and type-2 diabetes mellitus (2) and has been proposed to play a role in the pathogenesis of diabetic nephropathy (3). Obesity is one of the defining criteria of the metabolic syndrome as proposed by the National Cholesterol Education Program Adult Treatment Panel III (4) and the World Health Organization (5). The metabolic syndrome, which is characterized by the concurrent existence of obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, and hypertension, has been shown to be a strong and independent risk factor for cardiovascular, and all cause mortality (6, 7) as well as the development of microalbuminuria and chronic kidney disease (8).Obesity is considered a major generator of metabolic syndrome (9). Early in the course of obesity-initiated metabolic syndrome, structural and functional changes similar to diabetic kidney disease occur (10). These changes include glomerular hyperfiltration, glomerular basement membrane thickening, mesangial cell proliferation, mesangial matrix thickening, and expansion of Bowman's capsule (10) and are considered precursors to more severe renal injury. Severe obesity has been associated with the eventual development of focal and segmental glomerulosclerosis (11). Although incompletely understood, several hemodynamic, hormonal, and metabolic factors have been proposed to contribute to t...

Our results indicated that there was an age-related increase in renal expression of SREBP-1 and SREBP-2 with resultant increases in lipid synthesis and triglyceride and cholesterol accumulation in the kidney. Because we have previously shown that increased expression of SREBPs in the kidney per se results in glomerulosclerosis and proteinuria, our data suggested that increased SREBPs' expression resulting in increased renal lipid accumulation may play an important role in age-related nephropathy.

Sterol regulatory element binding proteins (SREBP) are major regulators of fatty acid and cholesterol synthesis. This study found that age-related renal matrix deposition and proteinuria were associated with increased renal expression of SREBP-1 and SREBP-2 and increased renal accumulation of triglyceride and cholesterol. Because calorie restriction (CR) modulates age-related renal disease, it then was determined whether the effects of CR are mediated partially by modulation of renal lipid metabolism. Compared with ad libitum (AL)-fed 24-month-old (24m) F344BN rats, CR resulted in significant decreases in extracellular matrix accumulation (periodic acid-Schiff staining and immunofluorescence of type IV collagen and fibronectin) and proteinuria. A significant decrease was also observed in the renal expression of growth factors (connective tissue growth factor and vascular endothelial growth factor) and matrix metalloproteinase inhibitor (plasminogen activator inhibitor-1). These structural and functional changes were associated with significant decreases in renal nuclear SREBP-1 (5.2 in 24m AL versus 3.3 densitometry units in 24m CR; P < 0.01) and SREBP-2 (7.1 in 24m AL versus 4.1 densitometry units in 24m CR; P < 0.01) protein abundance and renal triglyceride and cholesterol contents. It is interesting that serum leptin level was significantly increased as a function of aging, and CR resulted in significant reduction in serum leptin level. Because it was shown previously that increased renal expression of SREBP-1a per se caused renal lipid accumulation, glomerulosclerosis, and proteinuria, the results suggest that CR modulates age-related renal disease in part by modulation of renal SREBP expression and renal lipid accumulation.