Calorie restriction modulates renal expression of sterol regulatory element binding proteins, lipid accumulation, and age-related renal disease.
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 (24 m) 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 24 m AL versus 3.3 densitometry units in 24 m CR; P < 0.01) and SREBP-2 (7.1 in 24 m AL versus 4.1 densitometry units in 24 m 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.
Jiang
Tao
T
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, 4200 East 9th Avenue, C281, Denver, CO 80262, USA.
Liebman
Scott E
SE
Lucia
M Scott
MS
Phillips
Carrie L
CL
Levi
Moshe
M
D000375:Aging; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D031204:Caloric Restriction; D002784:Cholesterol / Q000378:metabolism; D003720:Densitometry; D005109:Extracellular Matrix / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006031:Glycosylation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D020738:Leptin / Q000097:blood / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D020738:Leptin; D008055:Lipids; D017395:Plasminogen Activator Inhibitor 1; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D051779:Sterol Regulatory Element Binding Proteins; D014280:Triglycerides; D002784:Cholesterol