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.
Highlights
The incidence and mortality of chronic kidney disease (CKD) continue to increase, severely threatening human health.[1-3]
The results of ELISA showed that the levels of mindin were remarkably increased in the serum of mice after renal fibrosis (Figure 1F). These results suggest that mindin is an inducible renal tubule-derived protein that may play an important role in murine renal fibrosis pathogenesis
In the murine stroke models, mindin ablation could suppress cerebral ischaemia reperfusion-induced inflammation through inhibiting nuclear factor (NF)-κB pathway activation.[42]. Consistent with these findings, present research indicates that mindin overexpression promotes p65 translocation from the cytoplasm into the nucleus, leading to NF-κB pathway activation in vitro, while mindin disruption deactivates the NF-κB pathway in mice after renal ischaemia reperfusion injury (IRI); this suggests that mindin might exacerbate renal damage, at least partially, through regulating the NF-κB signalling pathway in the progress of renal fibrosis
Summary
The incidence and mortality of chronic kidney disease (CKD) continue to increase, severely threatening human health.[1-3]. Western blots of nuclear proteins in HK-2 cells analysis indicated that mindin overexpression significantly enhanced p65 expression in the pLV-Mindin group cells with stimulus than that in control and pLV-Vector group cells (Figure 2G and H) These results suggest that the NF-κB signalling pathway was activated and may be linked with mindin in renal fibrosis in vitro. To define the underlying effect of mindin on renal fibrosis using an in vitro model, Western blot was performed to test the expression levels of ECM-related proteins like Fn, E-Cadherin and collagen I (Figure 3A). Mindin loss attenuated TGF-β, p-Smad[2], as well as p-Smad[3] expressions and promoted Smad[7] protein level compared with that in sham group mice after renal IRI These results suggest mindin can reduce ECM-related proteins production through suppressing TGF-β/Smad pathway in the murine kidney after renal IRI
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