Role of altered renal lipid metabolism and the sterol regulatory element binding proteins in the pathogenesis of age-related renal disease

Abstract

Background. There are well-known changes in age-related renal function and structure, including glomerulosclerosis and decline in glomerular filtration rate (GFR). The purpose of this study was to identify a potential role for lipids in mediating age-related renal disease. Methods. Mice of five different age groups (3, 6, 12, 19, and 23 months old) were studied. Results. We have found that in C57BL/6 mice there was a progressive increase in age-related glomerulosclerosis [increase in periodic acid-Schiff (PAS) staining and accumulation of extracellular matrix proteins including type IV collagen and fibronectin], increased glomerular basement thickness and podocyte width and effacement, and increased proteinuria. These changes were associated with age-related increase in lipid accumulation as determined by increased Oil Red O staining in kidney sections. Biochemical analysis indicated that these lipid deposits corresponded to significant increases in renal triglyceride and cholesterol content. We have also found significant age-related increases in the nuclear transcription factors, sterol regulatory element-binding proteins (SREBP-1 and SREBP-2), protein abundance and increased expression or activity of their target enzymes that play an important role in lipid synthesis. Conclusion. 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. © 2005 by the International Society of Nephrology.