Abstract
BackgroundChronic kidney disease (CKD) is characterized by high morbidity and mortality and is difficult to cure. Renal interstitial fibrosis (RIF) is a major determinant of, and commonly occurs within, CKD progression. Epithelial mesenchymal transition (EMT) has been identified as a crucial process in triggering renal interstitial fibrosis (RIF). Interleukin‐like EMT inducer (ILEI) is an important promotor of EMT; this study aims to elucidate the mechanisms involved.MethodsMale C57BL6/J mouse were randomly divided into 6 groups: sham (n = 10), sham with negative control (NC) shRNA (sham + NC, n = 10), sham with ILEI shRNA (sham + shILEI, n = 10), unilateral ureteral obstruction (UUO, n = 10), UUO with NC (UUO + NC, n = 10) and UUO with ILEI shRNA (UUO + shILEI, n = 10). Hematoxylin and eosin (H&E), Masson, and immunohistochemical (IHC) staining and western blotting (WB) were performed on murine kidney tissue to identify the function and mechanism of ILEI in RIF. In vitro, ILEI was overexpressed to induce EMT in HK2 cells and analyzed via transwell, WB, real-time PCR, and co-immunoprecipitation. Finally, tissue from 12 pediatric CKD patients (seven with RIF and five without RIF) were studied with H&E, Masson, and IHC staining.ResultsOur in vitro model revealed that ILEI facilitates RIF in the UUO model via the Akt and ERK pathways. Further experiments in vivo and in vitro revealed that ILEI promotes renal tubular EMT by binding and activating leukemia inhibitory factor receptor (LIFR), in which phosphorylation of Akt and ERK is involved. We further find markedly increased expression levels of ILEI and LIFR in kidneys from pediatric CKD patients with RIF.ConclusionOur results indicate that ILEI may be a useful biomarker for renal fibrosis and a potential therapeutic target for modulating RIF.
Highlights
Chronic kidney disease (CKD) is a public health problem with increasing global prevalence
Interleukin‐like EMT inducer (ILEI) facilitates Epithelial mesenchymal transition (EMT) and Renal interstitial fibrosis (RIF) in the UUO mouse model We first verified the effect of shRNA-induced silencing of ILEI in mice of through western blotting (WB) and real-time PCR, showing that ILEI protein and mRNA expression decreased significantly following shRNA injection into the mice (Fig. 1A– C)
Comparing UUO and UUO + negative control (NC) with UUO + shILEI showed that the EMT-related indicators all reversed after ILEI silencing, indicating that ILEI plays a catalytic role in EMT (Fig. 1D, E)
Summary
Chronic kidney disease (CKD) is a public health problem with increasing global prevalence (about 10–13% of the population [1, 2]). Interleukin-like EMT inducer (ILEI), a member of the family with sequence similarity 3 (FAM3) family, is widely expressed in human and mouse tissues and plays important roles in a variety of biological processes. It was originally discovered as a pivotal gene for Alzheimer’s disease [8] and is a key factor in retinal formation [9, 10]. Renal interstitial fibrosis (RIF) is a major determinant of, and commonly occurs within, CKD progression. Epithelial mesenchymal transition (EMT) has been identified as a crucial process in triggering renal interstitial fibrosis (RIF). Interleukin‐like EMT inducer (ILEI) is an important promotor of EMT; this study aims to elucidate the mechanisms involved
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