Calorie Restriction Modulates Renal Expression of Sterol Regulatory Element Binding Proteins, Lipid Accumulation, and Age-Related Renal Disease

Abstract

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.

Age-specific effects of short- and long-term caloric restriction on the expression of adiponectin and adiponectin receptors: Influence of intensity of food restriction

“…Similar to the results obtained for the adiponectin expression and release into the plasma, senescent rats did not show a significant decrease of cardiac (and liver) triglycerides in response to the stimulatory effects of moderate caloric restriction as described before in kidneys from senescent Fischer 344 rats (Jiang et al, 2005), while the stronger stimulus (6 months, -40%) was sufficient in old and in young animals. Others have also shown that 1 week of moderate caloric restriction in young rats did not affect the triglyceride content while after 3 weeks muscular but not liver triglyceride content was reduced .…”

654 Beneficial Effects of Alternate Dietary Regimen on Liver Inflammation, Atherosclerosis and Renal Activation

“…Moreover, enhanced expression of MCP-1 in conjunction with significant renal macrophage infiltrates, particularly in the glomeruli, was observed in the HC and MC groups but was absent in the ALT group. These observations are in line with previous studies employing calorie restriction diets showing significant reductions in glomerular VCAM expression [17], renal monocyte/macrophage infiltration, mesangial expansion [18], and development of proteinuria [19].…”

Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

“…In one group of animals (n ϭ 8 in each experimental group), after anesthesia (intraperitoneal injection of pentobarbital; Abbott Laboratories, Chicago, IL), blood was drawn from the inferior vena cava, and then the kidneys were removed and processed for biochemical studies that included 1) RNA extraction and real-time quantitative PCR, 2) isolation of nuclei and microsomes and Western blotting, 3) measurement of stearoyl CoA desaturase-1 (SCD-1) enzyme activity, and 4) lipid extraction and lipid composition analysis. In another group of animals (n ϭ 4 in each experimental group), after anesthesia, the kidneys were fixed via in vivo perfusion fixation and the kidneys were processed for 1) periodic acid Schiff (PAS) stain for renal histopathology, 2) oil red O stain for neutral lipids, and 3) immunofluorescence microscopy for extracellular matrix proteins (5,6,12,18,19).…”

“…Urine creatinine concentration was determined by Jaffe's reaction of alkaline picrate with creatinine using a Creatinine Companion kit (Exocell). Results were expressed as the urine albumin-to-creatinine ratio (micrograms per milligram) (5,6,12,18,19). Total RNA extraction and real-time PCR.…”

“…Cyclophilin was used as internal control, and the amount of RNA was calculated by the comparative C T method. All data were calculated from duplicate reactions, as we have previously described (5,6,12,18,19). Primers used are listed in Table 1.…”