DPP4/CD32b/NF-κB Circuit: A Novel Druggable Target for Inhibiting CRP-Driven Diabetic Nephropathy.

Abstract

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, but treatment remains ineffective. C-reactive protein (CRP) is pathogenic in DN, which significantly correlated with dipeptidyl peptidase-4 (DPP4) expression in diabetic patients with unknown reason. Here, using our unique CRPtg-db/db mice, we observed human CRP markedly induced renal DPP4 associated with enhanced kidney injury compared with db/db mice. Interestingly, linagliptin, a US Food and Drug Administration (FDA)-approved specific DPP4 inhibitor, effectively blocked this CRP-driven DN in the CRPtg-db/db mice. Mechanistically, CRP evoked DPP4 in cultured renal tubular epithelial cells, where CD32b/nuclear factor κB (NF-κB) signaling markedly enriched p65 binding on the DPP4 promoter region to increase its transcription. Unexpectedly, we further discovered that CRP triggers dimerization of DPP4 with CD32b at protein level, forming a novel DPP4/CD32b/NF-κB signaling circuit for promoting CRP-mediated DN. More importantly, linagliptin effectively blocked the circuit, thereby inhibiting the CRP/CD32b/NF-κB-driven renal inflammation and fibrosis. Thus, DPP4 may represent a precise druggable target for CRP-driven DN.

• Authors: Patrick Ming-Kuen Tang, Ying-Ying Zhang, Jessica Shuk-Chun Hung, Jeff Yat-Fai Chung, Xiao-Ru Huang, Ka-Fai To, Hui-Yao Lan
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 1 Pg. 365-375 (01 06 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 32956626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Fc gamma receptor IIB
• NF-kappa B
• Receptors, IgG
• C-Reactive Protein
• Dipeptidyl Peptidase 4
• Dpp4 protein, mouse

Topics

• Animals
• Biomarkers
• C-Reactive Protein (metabolism)
• Diabetes Mellitus, Experimental
• Diabetic Nephropathies (etiology, metabolism, pathology)
• Dipeptidyl Peptidase 4 (metabolism)
• Disease Models, Animal
• Disease Susceptibility
• Gene Expression Regulation
• Mice
• NF-kappa B (metabolism)
• Receptors, IgG (metabolism)
• Signal Transduction