A novel fusion protein consisting of anti-ANGPTL3 antibody and interleukin-22 ameliorates diabetic nephropathy in mice

作者全名："Ma, Qianqian; Hu, Xiaozhi; Liu, Fangyu; Cao, Zhonglian; Han, Lei; Zhou, Kaicheng; Bai, Yu; Zhang, Yuting; Nan, Yanyang; Lv, Qianying; Rao, Jia; Wu, Tao; Yang, Xue; He, Haidong; Ju, Dianwen; Xu, Hong"

作者地址："[Ma, Qianqian; Lv, Qianying; Rao, Jia; Xu, Hong] Fudan Univ, Childrens Hosp, Natl Childrens Med Ctr, Shanghai, Peoples R China; [Hu, Xiaozhi; Cao, Zhonglian; Han, Lei; Zhou, Kaicheng; Bai, Yu; Zhang, Yuting; Nan, Yanyang; Wu, Tao; Yang, Xue; Ju, Dianwen] Fudan Univ, Sch Pharm, Dept Biol Med, Shanghai, Peoples R China; [Hu, Xiaozhi; Cao, Zhonglian; Han, Lei; Zhou, Kaicheng; Bai, Yu; Zhang, Yuting; Nan, Yanyang; Wu, Tao; Yang, Xue; Ju, Dianwen] Fudan Univ, Shanghai Engn Res Ctr Immunotherapeut, Sch Pharm, Shanghai, Peoples R China; [Liu, Fangyu] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing, Peoples R China; [He, Haidong; Ju, Dianwen] Fudan Univ, Minhang Hosp, Dept Nephrol, Shanghai, Peoples R China"

通信作者："Xu, H (通讯作者)，Fudan Univ, Childrens Hosp, Natl Childrens Med Ctr, Shanghai, Peoples R China.; Ju, DW (通讯作者)，Fudan Univ, Sch Pharm, Dept Biol Med, Shanghai, Peoples R China.; Ju, DW (通讯作者)，Fudan Univ, Shanghai Engn Res Ctr Immunotherapeut, Sch Pharm, Shanghai, Peoples R China.; He, HD; Ju, DW (通讯作者)，Fudan Univ, Minhang Hosp, Dept Nephrol, Shanghai, Peoples R China."

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000899666200001

JCR分区：Q1

影响因子：7.3

年份：2022

卷号：13

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：angiopoietin-like protein 3; interleukin-22; fusion protein; diabetic nephropathy DN; diabetic nephropathy; podocyte injury; inflammatory response

摘要："IntroductionThe pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin alpha v beta 3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism. MethodsGenes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks. ResultsIn this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-kappa B) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN. ConclusionCollectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery."

基金机构：National Natural Science Foundation of China [82170793]; Collaborative Research Projects of Greater Bay Area Institute of Precision Medicine (Guangzhou) in 2021 [IPM2021C003]

基金资助正文：This research was funded by the National Natural Science Foundation of China under grant 82170793 and The Collaborative Research Projects of Greater Bay Area Institute of Precision Medicine (Guangzhou) in 2021 (IPM2021C003).