PODOCYTE-SPECIFIC OVEREXPRESSION OF SIRT-1 INCREASES NEPHRIN IN OBESE MICE FED A HIGH-FAT DIET

Abstract

Obesity can lead to inflammation, hyperlipidemia, diabetes, hypertension, and renal dysfunction, and is also associated with proteinuria. Histopathological changes in the glomeruli in obesity were characterized by glomerulomegaly and focal segmental glomerulosclerosis. This study was designed to investigate the effect of sirtuin 1 (SIRT-1), podocyte-specific overexpressed, on nephrin levels in obese mice induced by high fat diet. SIRT-1 has been proposed as a chemotherapeutic target for type II diabetes mellitus. After establishing the SIRT-1 transgenic mice, experimental groups were divided into following three groups: Normal diet-normal group (ND-NL), high fat diet-normal group (HFD-NL), and high fat diet-SIRT-1 group (HFD-SIRT1). The background of transgenic mice was C57BL/6. High fat diet group were fed with a high calorie diet (60%) for up to 21 weeks to examine a progressive development of obesity. Body weight, 6 hours fasting blood glucose, and HbA1c were regularly measured. Albumin-Creatinine Ratio (ACR) in 24 hours urine was measured 21 weeks after the experiment. The expression levels of SIRT-1 and nephrin in the kidney by using western-blot and RT-PCR were compared. With repeated measures ANOVA test, both high fat diet groups were showing that the body weight was significantly higher than normal diet group (P<0.0001) and showing that 6 hours fasting blood glucose was also significantly different (P<0.05). Although statistically not different, urinary ACR of the HFD-SIRT1 group was lower than the HFD-NL group (P=0.09). The nephrin protein expression in the HFD-SIRT1 group was significantly increased than the HFD-NL (P<0.05). The nephrin mRNA level in the HFD-SIRT1 group showed a tendency to increase compared with the HFD-NL group. Taken together the results, deterioration of the kidney disease caused by obesity and hyperglycemia could be prevented by increasing the level of the nephrin expression through SIRT-1 activation. SIRT-1 may have the ability to protect the podocyte from injuries caused by obesity and hyperglycemia.