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Exosomal miR-122-5p from tubular cells ameliorates renal interstitial fibrosis by regulating fibroblasts via HIF-1α

ABSTRACT: Renal interstitial fibrosis (RIF) is a common pathological feature and final manifestation of chronic progressive kidney disease. Although exosome-mediated intercellular communication is known to play a crucial role in RIF, the mechanism by which injured tubular epithelial cells (TECs) contribute to fibrogenesis remains incompletely understood. In this study, we investigated the role of exosomal miR-122-5p derived from TECs in modulating fibroblast activation and renal fibrosis. Exosomes were isolated from kidneys of unilateral ureteral obstruction (UUO) mice and from TGF-β1-stimulated HK-2 cells. These exosomes were either co-cultured with fibroblasts (NRK-49F cells) or injected into UUO mice via the tail vein. High-throughput miRNA profiling was used to identify differentially expressed miRNAs in exosomes derived from HK-2 cells, and miR-122-5p was selected for further investigation based on expression level and bioinformatic prediction. Functional analyses were performed using miRNA mimics, inhibitors, and target validation assays. The results showed that exosomal miR-122-5p was significantly downregulated in both fibrotic kidneys and TGF-β1-induced HK-2 cells. In vivo and in vitro, restoration of miR-122-5p levels markedly attenuated renal fibrosis, as evidenced by the reduction of fibrotic markers including α-smooth muscle actin, fibronectin, and collagen I. Mechanistically, miR-122-5p was found to directly target hypoxia-inducible factor 1-alpha (HIF-1α), thereby inhibiting activation of the TGF-β1/Smad signaling pathway. These findings suggest that decreased expression of miR-122-5p in TEC-derived exosomes promotes renal fibrosis through the HIF-1α/TGF-β1/Smad axis, while reintroduction of miR-122-5p can effectively reverse these effects. Taken together, our study provides new insights into the intercellular communication between TECs and fibroblasts via exosomal miRNAs, and identifies miR-122-5p as a potential therapeutic target for the treatment of renal interstitial fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305699 | GEO | 2025/09/19

REPOSITORIES: GEO

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Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.

Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. FFPE kidney specimens (n=25) including baseline and repeated needle renal biopsies were from 14 patients with LN enrolled in IRB-approved protocols at the NIDDK between 1976 and 1999. The specimens were divided in two groups based on histological chronicity index (CI). CI ≥ 4 were categorized as having high degree of chronicity of chronic kidney injury. 18 kidneys from 8 patients including high CI (n=9) and low CI (n=9) were used for miR profiling by Affymetrix microRNA microarrays.

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Exosomal miR-122-5p from tubular cells ameliorates renal interstitial fibrosis by regulating fibroblasts via HIF-1α

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