Mannose‐binding lectin activates the nuclear factor‐κB and renal inflammation in the progression of diabetic nephropathy

• DOI: 10.1096/fj.202101852r
• Publication Date: 2022-02-23T16:13:47Z
• Authors: Yanhong Ma; Fanghao Cai; Xiaohan Huang; Huijing Wang; Binfeng Yu; Junni Wang; Wanyun Nie; Kedan Cai; Yi Yang; Jianghua Chen; Liang Xiao; Fei Han
• Keywords: Inflammation; Male; 0303 health sciences; Macrophages; Interleukin-1beta; NF-kappa B; Kidney; Mannose-Binding Lectin; 3. Good health; Mice; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Mutation; Animals; Humans; Diabetic Nephropathies; Female; Cells, Cultured

Increased serum mannose-binding lectin (MBL) level has been proven to correlate with the development of diabetic nephropathy (DN). Here, we aim to find the role and mechanism of MBL involved in the progression of DN. Patients with DN were recruited and divided into two groups according to different rs1800450 genotypes of the MBL2 gene, and inflammatory profiles in monocytes/macrophages were compared between the two groups. MBL was given to treat macrophages, HK2, and HMC, and a co-culture transwell system was then employed. Renal inflammation and fibrosis parameters were measured after knocking down or overexpressing MBL genes in mice. Proinflammatory profile, manifesting as enhanced IL-1β production and M1 polarization, was found in monocytes/macrophages from DN with a rs1800450 GG genotype of MBL2 gene who had higher MBL level, compared with those with a rs1800450 GA genotype. In mechanism, MBL directly induced inflammatory responses in macrophages, which promoted inflammatory and fibrotic markers in HK2 and HMCs during co-culture. Further experiments showed that MBL can promote macrophages transforming to the M1 subset mainly by activating the nuclear factor-κB pathway. After downregulation of MBL, the blood glucose, triglyceride, urine protein, injuries of glomerulus and tubules, and the degree of renal inflammation and fibrosis were ameliorated in db/db mice treated with AAV-MBL1/2-shRNA. Overexpression of MBL promoted macrophage infiltration in the kidney. In conclusion, MBL is a crucial mediator in the progression of DN via activating the nuclear factor-κB pathway in macrophages. This will serve as a genetic base for some patients with DN who have poor outcomes and provide a direction for the screening.