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

Yilan Shen; Wei Chen; Lei Han; Qi Bian; Jiajun Fan; Zhonglian Cao; Xin Jin; Tao Ding; Zongshu Xian; Zhiyong Guo; Wei Zhang; Dianwen Ju; Xiaobin Mei

doi:10.1016/j.apsb.2020.07.002

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

Acta Pharm Sin B. 2021 Jan;11(1):127-142. doi: 10.1016/j.apsb.2020.07.002. Epub 2020 Jul 13.

Authors

Yilan Shen¹, Wei Chen^{2

3}, Lei Han², Qi Bian¹, Jiajun Fan², Zhonglian Cao², Xin Jin², Tao Ding¹, Zongshu Xian², Zhiyong Guo¹, Wei Zhang⁴, Dianwen Ju², Xiaobin Mei¹

Affiliations

¹ Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
² Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China.
³ Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
⁴ Department of Nephrology, Shanghai Yangpu Hospital of TCM, Shanghai 200090, China.

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.

Keywords: 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; Diabetic nephropathy; ECM, extracellular matrix; ESRD, end-stage renal disease; FA, fatty acid; FATPs, fatty acid transport proteins; Fusion protein; GBM, glomerular basement membrane; GSEA, gene set enrichment analysis; H&E, hematoxylin & eosin; HbA1c%, glycosylated hemoglobin; IL-22, interleukin-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; Vascular endothelial growth factor B; eGFR, estimated glomerular filtration rate; β2-MG, β2 microglobulin.