Recent studies have demonstrated that chronic
inflammation-induced lymphangiogenesis plays a crucial role in the progression of various renal diseases, including
diabetic nephropathy.
SAR131675 is a selective vascular endothelial cell
growth factor receptor-3 (VEGFR-3)-tyrosine
kinase inhibitor that acts as a
ligand for
VEGF-C and
VEGF-D to inhibit lymphangiogenesis. In this study, we evaluated the effect of
SAR131675 on renal lymphangiogenesis in a mouse model of
type 2 diabetes. Male C57BLKS/J db/m and db/db mice were fed either a regular chow diet or a diet containing
SAR131675 for 12 weeks from 8 weeks of age. In addition, we studied
palmitate-induced lymphangiogenesis in human kidney-2 (HK2) cells and RAW264.7 monocytes/macrophages, which play a major role in lymphangiogenesis in the kidneys. SAR131475 ameliorated
dyslipidemia,
albuminuria, and
lipid accumulation in the kidneys of db/db mice, with no significant changes in
glucose and
creatinine levels and
body weight. Diabetes-induced systemic
inflammation as evidenced by increased systemic
monocyte chemoattractant protein-1 and
tumor necrosis factor-α level was decreased by SAR131475. SAR131475 ameliorated the accumulation of
triglycerides and
free fatty acids and reduced
inflammation in relation to decreased
chemokine expression and pro-inflammatory M1 macrophage infiltration in the kidneys. Downregulation of
VEGF-C and
VEGFR-3 by SAR131475 inhibited lymphatic growth as demonstrated by decreased expression of LYVE-1 and podoplanin that was further accompanied by reduced tubulointerstitial
fibrosis, and
inflammation in relation to improvement in oxidative stress and apoptosis. Treatment with SAR131475 improved
palmitate-induced increase in the expression of
VEGF-C,
VEGFR-3, and LYVE-1, along with improvement in cytosolic and mitochondrial oxidative stress in RAW264.7 and HK2 cells. Moreover, the enhanced expression of M1 phenotypes in RAW264.7 cells under
palmitate stress was reduced by SAR131475 treatment. The results suggest that modulation of lymphatic proliferation in the kidneys is a new treatment approach for type 2
diabetic nephropathy and that
SAR131675 is a promising
therapy to ameliorate renal damage by reducing lipotoxicity-induced lymphangiogenesis.