4.7 Article

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

期刊

FASEB JOURNAL
卷 36, 期 3, 页码 -

出版社

WILEY
DOI: 10.1096/fj.202101852R

关键词

diabetic nephropathy; macrophage; mannose-binding lectin; nuclear factor-kappa B

资金

  1. National key R&D Program of China [2018YFC1314003]
  2. National Natural Science Foundation of China (NSFC) [81770674]
  3. Primary Research and Development Plan of Zhejiang Province [2020C03034]

向作者/读者索取更多资源

Increased serum mannose-binding lectin (MBL) level has been proven to correlate with the development of diabetic nephropathy (DN). This study found that MBL promotes the progression of DN by activating the nuclear factor-kappa B pathway in macrophages. This finding provides a new direction for the treatment of DN patients.
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-1 beta 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-kappa B 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-kappa B 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.

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