Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice

National Science Foundation of China [30770490]; 973 Program of China [2009CB941601]; Science Planning Program of Fujian Province [2009J1010]; Natural Science Foundation of Fujian Province [2009J01180]; Fujian Provincial Department of Science and TechnoloThe aim of the study was to investigate the effects of genetic deficiency of aldose reductase in mice on the development of key endpoints of diabetic nephropathy. A line of Ar (also known as Akr1b3)-knockout (KO) mice, a line of Ar-bitransgenic mice and control C57BL/6 mice were used in the study. The KO and bitransgenic mice were deficient for Ar in the renal glomeruli and all other tissues, with the exception of, in the bitransgenic mice, a human AR cDNA knockin-transgene that directed collecting-tubule epithelial-cell-specific AR expression. Diabetes was induced in 8-week-old male mice with streptozotocin. Mice were further maintained for 17 weeks then killed. A number of serum and urinary variables were determined for these 25-week-old mice. Periodic acid-Schiff staining, western blots, immunohistochemistry and protein kinase C (PKC) activity assays were performed for histological analyses, and to determine the levels of collagen IV and TGF-beta 1 and PKC activities in renal cortical tissues. Diabetes-induced extracellular matrix accumulation and collagen IV overproduction were completely prevented in diabetic Ar-KO and bitransgenic mice. Ar deficiency also completely or partially prevented diabetes-induced activation of renal cortical PKC, TGF-beta 1 and glomerular hypertrophy. Loss of Ar results in a 43% reduction in urine albumin excretion in the diabetic Ar-KO mice and a 48% reduction in the diabetic bitransgenic mice (p < 0.01). Genetic deficiency of Ar significantly ameliorated development of key endpoints linked with early diabetic nephropathy in vivo. Robust and specific inhibition of aldose reductase might be an effective strategy for the prevention and treatment of diabetic nephropathy

Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients

Background/Aims: Insulin resistance is a well-known phenomenon in uremia. Resistin, a recently discovered insulin inhibitor secreted by adipocytes, is associated with obesity and insulin resistance in mice. Adiponectin, also secreted by adipocytes, is known to reduce insulin resistance in humans. The aim of the present study was to address the hypothesis that changes in resistin or adiponectin serum levels may relate to body composition and to insulin resistance in patients with end-stage renal disease. Methods: In a cross-sectional study, 33 non-diabetic patients ( 24 males and 9 females, mean age 61.5 +/- 15.8 years) with end-stage renal disease on chronic hemodialysis (treatment duration 41 +/- 31 months) that lacked signs of infection were enrolled. The control group consisted of 33, matched for age, sex and body mass index (BMI), healthy volunteers ( 22 males, 11 females, mean age 62.6 +/- 12.1 years). BMI (kg/m(2)) was calculated from body weight and height. Body fat (%) was measured by means of bioelectrical impedance. Blood samples were taken always in the morning after a 12-hour fasting period before and after the hemodialysis session. Resistin and adiponectin serum concentrations were measured by enzyme immunoassays and insulin by an electrochemiluminescence immunoassay. The posttreatment values were corrected regarding the hemoconcentration. The homeostasis model assessment index (HOMA-R) was calculated as an estimate of insulin resistance from the fasting glucose and insulin serum levels. Results: Pre-treatment resistin serum levels were significantly increased in hemodialysis patients compared to healthy controls (19.2 +/- 6.2 vs. 3.9 +/- 1.8 ng/ml; p < 0.001). Hemodialysis did not alter resistin levels, as pre- and post-treatment levels were not different when corrected for hemoconcentration (19.2 +/- 6.2 vs. 18.7 +/- 5.0 ng/ml; p = 0.54). Adiponectin levels were also increased in hemodialysis patients compared to healthy controls (25.4 +/- 21.5 vs. 10.5 +/- 5.9 mu g/ml; p < 0.001). A significant inverse correlation was observed between the serum adiponectin levels before the hemodialysis session on the one hand and the BMI ( r = - 0.527, p = 0.002), the HOMA-R ( r = - 0.378, p < 0.05) and the fasting insulin levels ( r = - 0.397, p < 0.05) on the other. However, no significant correlation was observed between serum resistin levels on the one hand versus HOMA-R index (3.2 +/- 3.9 mmol center dot mu IU/ml; r = - 0.098, p = 0.59), insulin levels (13.3 +/- 14.4 mU/l; r = - 0.073, p = 0.69), glucose levels ( 89 +/- 13 mg/dl; r = - 0.049, p = 0.78), BMI (25.6 +/- 3.7 kg/m(2); r = - 0.041, p = 0.82) and body fat content (26.4 +/- 8.4%; r = - 0.018, p = 0.94) on the other hand. Conclusion: Resistin serum levels are significantly elevated in non-diabetic patients with end-stage renal disease that are treated by hemodialysis. The hemodialysis procedure does not affect the resistin levels. Along with previous observations in patients with renal insufficiency in the pre-dialysis stage, our findings implicate an important role of the kidney in resistin elimination. However, increased resistin serum levels in hemodialysis patients are not related to reduced insulin sensitivity encountered in uremia. Copyright (C) 2005 S. Karger AG, Basel