Hypoxia‐induced HE4 in tubular epithelial cells promotes extracellular matrix accumulation and renal fibrosis via NF‐κB

Abstract

Hypoxia-induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF-κB pathway through the NF-κB transcription-activating group P65 by phosphorylation and nuclear translocation.NF-κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia-induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF-κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF-1α/HE4/NF-κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia-induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies. K E Y W O R D Schronic hypoxia, extracellular matrix, human epididymis secretory protein 4, NF-κB, renal fibrosis

Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p

“…RF is characterized by the proliferation of interstitial fibroblasts, excessive deposition of extracellular matrix (ECM), and renal tubular atrophy [ 4 ]. Transforming growth factor-β (TGF-β) is an important growth factor that activates its downstream regulatory factor Smad protein.…”

Human Epididymis Protein 4 Expression in the Renal Cortex Tissue is an Independent Prognostic Factor in Patients with Renal Cell Carcinoma

“…This study also aimed to address how the expression of HE4 in the renal cortex affected the poor prognosis of RCC patients. Although the exact physiological and pathological functions of HE4 are poorly understood for several cancers and renal brosis, Zhang et al investigated the expression and mechanisms of HE4 in the pathogenesis of renal brosis by using the unilateral ureteral obstruction mouse model [16]. They found that hypoxia signi cantly increased HE4 expression in renal tubular epithelial cells.…”

Human Epididymis Protein 4 expression in the renal cortex tissue is an independent prognostic factor in patients with renal cell carcinoma

“…The high expression of HE4 in normal cortex can represent not only the onset of renal brosis but also EMT in RCC, which is a key process that promotes cancer invasion, distal metastasis and drug resistance [18]. Additionally, Zhang et al suggested HE4 in renal tubular epithelial cells was upregulated by hypoxia [15]. The tubular epithelial cells in normal cortex coexisting with RCC requiring blood supply is speculated to be under the hypoxic condition due to deprivation of blood ow.…”

“…Moreover, serum HE4 levels were found to be signi cantly increased in the early stages of CKD, and serum levels were also found to be correlated with the degree of renal brosis, suggesting that the upregulated expression of HE4 may present as one of the initial sign in the onset and progression of renal brosis [14]. Zhang et al investigated the expression and mechanisms of HE4 in the pathogenesis of renal brosis by using the unilateral ureteral obstruction mouse model [15]. They found that hypoxia signi cantly increased HE4 expression in renal tubular epithelial cells.…”