Mindin deficiency alleviates renal fibrosis through inhibiting NF-κB and TGF-β/Smad pathways

J Cell Mol Med. 2020 May;24(10):5740-5750. doi: 10.1111/jcmm.15236. Epub 2020 Apr 6.

Abstract

Renal fibrosis acts as a clinical predictor in patients with chronic kidney disease and is characterized by excessive extracellular matrix (ECM) accumulation. Our previous study suggested that mindin can function as a mediator for liver steatosis pathogenesis. However, the role of mindin in renal fibrosis remains obscure. Here, tumour necrosis factor (TGF)-β-treated HK-2 cells and global mindin knockout mouse were induced with renal ischaemia reperfusion injury (IRI) to test the relationship between mindin and renal fibrosis. In vitro, mindin overexpression promoted p65-the hub subunit of the NF-κB signalling pathway-translocation from the cytoplasm into the nucleus, resulting in NF-κB pathway activation in TGF-β-treated HK-2 cells. Meanwhile, mindin activated the TGF-β/Smad pathway, thereby causing fibrotic-related protein expression in vitro. Mindin-/- mice exhibited less kidney lesions than controls, with small renal tubular expansion, inflammatory cell infiltration, as well as collagen accumulation, following renal IRI. Mechanistically, mindin-/- mice suppressed p65 translocation and deactivated NF-κB pathway. Simultaneously, mindin disruption inhibited the TGF-β/Smad pathway, alleviating the expression of ECM-related proteins. Hence, mindin may be a novel target of renal IRI in the treatment of renal fibrogenesis.

Keywords: NF-κB pathway; TGF-β/Smad; inflammatory response; mindin; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Biopsy
  • Disease Models, Animal
  • Extracellular Matrix Proteins / deficiency*
  • Fibrosis
  • Gene Knockdown Techniques
  • Inflammation / etiology
  • Inflammation / metabolism
  • Kidney Diseases / etiology*
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology
  • Male
  • Mice
  • NF-kappa B / metabolism*
  • Signal Transduction*
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Biomarkers
  • Extracellular Matrix Proteins
  • NF-kappa B
  • Smad Proteins
  • Transforming Growth Factor beta
  • mindin