Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response

Abstract

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.

Roles of interleukins (interleukin-18 and interleukin-17a) and transforming growth factor-beta markers in the pathogenesis of diabetic kidney diseases

“…A study demonstrated that, in the DKD mouse model, blocking IL-17a signaling utilizing neutralizing antibodies manifested a potentiated impact on reducing nephropathy and improved renal functioning by reducing lipid accumulation. Therefore, the concurrent impediment of IL-17a might represent a new and efficient management approach (Cao et al ., 2023)[ 7 ] (Guedes and Pecoits-Filho, 2022). [ 25 ]…”

“…[ 5 ] Among these cytokines, interleukin (IL)-17a has been extensively studied for its involvement in autoimmune-mediated and inflammation-related disorders and may also contribute to renal inflammation damage (Li et al ., 2019). [ 6 ] Furthermore, other studies suggest that IL-17a is implicated in both acute and persistent nephropathy (Cao et al ., 2023)[ 7 ] (Chen et al ., 2022). [ 8 ]…”

Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value

“…Mehlem et al [ 50 ] found that VEGFB signaling is involved in regulating pathological lipid accumulation in diabetes, obesity, and cardiovascular disease and mainly affects mitochondrial genes related to the regulation of fatty acid intake. Cao et al [ 51 ] showed that VEGFB/IL-17 inhibits the expression of fatty acid transporters to reduce the accumulation of renal lipids and inhibit renal oxidative stress and mitochondrial dysfunction, thus improving the inflammatory response. Shen et al [ 52 ] also found that VEGFB/IL-22 can not only regulate glucose and lipid metabolism but also reduce inflammation and ROS accumulation.…”

Up-regulation of long non-coding RNA H19 ameliorates renal tubulointerstitial fibrosis by reducing lipid deposition and inflammatory response through regulation of the microRNA-130a-3p/long-chain acyl-CoA synthetase 1 axis

“…Ectopic lipid accumulation frequently occurs in tubulointerstitial fibrosis and the restoration of fatty acid metabolism protects against tubulointerstitial fibrosis [ 47 ]. In addition, ectopic lipid accumulation accelerates the proinflammatory response, which is also related to the development of tubulointerstitial fibrosis [ 48 ]. ACSL1 was down-regulated in obesity-associated nephropathy accompanied with increased lipid accumulation and triglyceride content [ 21 ].…”