Renoprotective Effect of the Recombinant Anti-IL-6R Fusion Proteins by Inhibiting JAK2/STAT3 Signaling Pathway in Diabetic Nephropathy

Nanwen Zhang; Qingmei Zheng; Yaduan Wang; Juan Lin; He Wang; Rui Liu; Mengru Yan; Xiaofeng Chen; Juhua Yang; Xiaole Chen

doi:10.3389/fphar.2021.681424

Renoprotective Effect of the Recombinant Anti-IL-6R Fusion Proteins by Inhibiting JAK2/STAT3 Signaling Pathway in Diabetic Nephropathy

Front Pharmacol. 2021 May 13:12:681424. doi: 10.3389/fphar.2021.681424. eCollection 2021.

Authors

Nanwen Zhang^{1

2}, Qingmei Zheng³, Yaduan Wang³, Juan Lin³, He Wang⁴, Rui Liu³, Mengru Yan³, Xiaofeng Chen⁵, Juhua Yang^{2

3}, Xiaole Chen^{2

3}

Affiliations

¹ School of Pharmacy, Department of Pharmacology, Fujian Medical University, Fuzhou, China.
² Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, China.
³ School of Pharmacy, Department of Bioengineering and Biopharmaceutics, Fujian Medical University, Fuzhou, China.
⁴ School of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
⁵ Rehabilitation Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Abstract

Diabetic nephropathy the main reason for end stage renal disease is a common microvascular complication in patients with type 1 and type 2 diabetes. The interleukin-6 (IL-6), acting as a pleiotropic cytokine, play key roles in main autoimmune disorders. The recombinant anti-IL-6R fusion proteins (VHH-0031) constructed and obtained in our lab is a dual target-directed single domain-based fusion protein against the interleukin-6 receptor. This study aims to explore the renoprotective effect of VHH-0031 in diabetic nephropathy. VHH-0031 treatment alleviated renal inflammation, morphologic injury and renal insufficiency in both Goto-Kakizaki rats and STZ-induced Sprague Dawley rats. These renoprotective effects of VHH-0031 are associated with alleviating inflammation and suppression of the JAK2/STAT3 signaling pathway. The mesangial cells treated with VHH-0031 exhibited anti-proliferation, anti-inflammation and inactivation of JAK2/STAT3 pathway under high glucose condition. In conclusion, this study demonstrates that VHH-0031 exhibited a potent protective effect in kidney of diabetic rats and its mechanism may be concerned with the inhibition of the IL-6R/JAK2/STAT3 pathway of glomerular mesangial cells.

Keywords: GK rat; IL-6; JAK2/STAT3; STZ; diabetic nephropathy.