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Abstract: TH-PO667

Role of Endothelial Leptin Receptor in the Development of Renal Injury Induced by a High Fat Diet

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Urai, Hidenori, Keio University School of Medicine, Tokyo, Japan
  • Kanda, Takeshi, Keio University School of Medicine, Tokyo, Japan
  • Kurokochi, Arata, Keio University School of Medicine, Tokyo, Japan
  • Kitahama, Rina, Keio University School of Medicine, Tokyo, Japan
  • Wakino, Shu, Keio University School of Medicine, Tokyo, Japan
  • Itoh, Hiroshi, Keio University School of Medicine, Tokyo, Japan
Background

Obesity and type 2 diabetes promotes endothelial dysfunction, which contributes to the progression of chronic kidney disease. Leptin is secreted from adipocyte and decreases body weight by controlling energy expenditure and food intake. Leptin-deficient ob/ob mice and leptin receptor (ObR)-deficient db/db mice are prone to glomerulosclerosis. However, the effect of leptin on renal injury is controversial and the site target of leptin action in the kidney has not been fully elucidated. In this study, we examined the role of ObR in the endothelium on glomerulosclerosis on high fat diet.

Methods

Using the Cre/loxP system, vascular endothelial (VE)-cadherin-Cre transgenic mice were crossed with ObRflox/flox mice to generate vascular endothelial ObR deficient mice (EC-KO mice). EC-KO mice and control ObRflox/flox without Cre (EC-WT) mice were fed on standard diet or 45% high-fat diet for 24 weeks. Urinary albumin, blood pressure and pathological findings were examined. The We evaluated gene expressions in isolated microvascular endothelial cells from EC-WT and EC-KO mice were also evaluated.

Results

The expression of ObR was detected in glomerulus and peritubular capillaries in EC-WT mice while its expression was not detected in EC-KO mice. When comparing EC-WT with EC-KO on high fat diet, Tthere was no significant difference in body weight, kidney weight, blood pressure and serum parameters between EC-WT and EC-KO on high fat diet,. However, high fat diet-induced increase in urinary albumin excretion was significantly lower in EC-KO mice (0.453 ± 0.064 g/gCr) compared with EC-WT mice (0.656 ± 0.052 g/gCr). High fat diet-induced glomerular hypertrophy was also ameliorated in EC-KO mice compared with EC-WT mice (2874 ± 110 μm2 vs. 3269 ± 129 μm2, n=6). Glomerular sclerosis, evaluated by masson's trichrome staining, was significantly reduced in EC-KO mice. The tissue fibrosis was also reduced in EC-KO mice. In addition,The expression of TGFβ1 and PAI-1, which are known for promoting fibrosis and downstream target of leptin, were significantly decreased in primary endothelial cells from EC-KO mice.

Conclusion

These data suggest that leptin exacerbates renal injury through the development of glomerular hyperfiltration and endothelial induction of TGFβ1 and PAI-1 genes.