ORIGINAL ARTICLE
VEGF-B antibody and interleukin-22 fusion protein ameliorates diabetic nephropathy through inhibiting lipid accumulation and inflammatory responses

https://doi.org/10.1016/j.apsb.2020.07.002Get rights and content
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Abstract

Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.

Graphical abstract

The expression of VEGF-B was increased and that of IL-22 was decreased in diabetic nephropathy (DN) patients. Anti-VEGFB/IL22 fusion protein combining VEGF-B antibody and IL22 ameliorated DN by alleviating ectopic lipid accumulation, inflammatory responses and insulin resistance.

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KEY WORDS

Diabetic nephropathy
Vascular endothelial growth factor B
Interleukin-22
Fusion protein

Abbreviations

ACR
urine albumin-to-creatinine ratio
ADFP
adipocyte differentiation-related protein
AGEs
advanced glycation end products
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
Ccr
creatinine clearance rate
DN
diabetic nephropathy
ECM
extracellular matrix
eGFR
estimated glomerular filtration rate
ESRD
end-stage renal disease
FA
fatty acid
FATPs
fatty acid transport proteins
GBM
glomerular basement membrane
GSEA
gene set enrichment analysis
H&E
hematoxylin & eosin
HbA1c%
glycosylated hemoglobin
IL-22
interleukin-22
KEGG
Kyoto Encyclopedia of Genes and Genomes
NAC
N-acetyl-l-cysteine
NLRP3
NOD-like receptor family pyrin domain-containing protein 3
NRP-1
neuropilin-1
PAS
periodic acid-Schiff
ROS
reactive oxygen species
SDS-PAGE
SDS-polyacrylamide gel electrophoresis
TEM
transmission electron microscopy
VEGF-B
vascular endothelial growth factor B
VEGFR
vascular endothelial growth factor receptor
β2-MG
β2 microglobulin

Cited by (0)

Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.

These authors made equal contributions to this work.