The pathogenesis of
diabetic kidney disease (DKD) is complicated. Current clinical treatments fail to achieve satisfactory efficacy in the prevention of DKD progression, it urgently needs novel and effective treatment for DKD. In this study, we firstly demonstrated that renal lipid metabolism abnormality and
inflammation significantly changed in DKD conditions by mining public transcriptomic data of DKD patient samples. KEGG analysis further exhibited the critical role of
vascular endothelial growth factor B (
VEGF-B) and
interleukin 17A (IL-17A) signal pathways in DKD progression, indicating that
VEGF-B and
IL-17A might be the promising targets for DKD treatment. Then the potential of a novel combination
therapy, anti-
VEGF-B plus anti-IL-17A antibody, was evaluated for DKD treatment. Our results demonstrated that simultaneous blockade of
VEGF-B and
IL-17A signaling with their
neutralizing antibodies alleviated renal damage and ameliorated renal function. The therapeutic effectiveness was not only related to the reduced
lipid deposition especially the neutral
lipids in kidney but also associated with the decreased
inflammation response. Moreover, the
therapy alleviated renal
fibrosis by reducing
collagen deposition and the expression of
fibronectin and α-SMA in kidney tissues.
RNA-seq analysis indicated that differential expression genes (DEGs) in db/db mice were significantly clustered into lipid metabolism,
inflammation,
fibrosis and DKD pathology-related pathways, and 181 of those DEGs were significantly reversed by the combinatory treatment, suggesting the underlying mechanism of administration of anti-
VEGF-B and anti-IL-17A
antibodies in DKD treatment. Taken together, this study identified that renal lipid metabolism abnormality and
inflammation were critically involved in the progression of DKD, and simultaneous blockade of
VEGF-B and
IL-17A signaling represents a potential DKD therapeutic strategy.