The Positive Feedback Loop of HIF-1α/miR-295/FIH-1 in Hyperuricemic Nephropathy
Plain Language Summary Background: Hyperuricemia is a common metabolic disorder and a risk factor for multiple diseases, including CKD. Hyperuricemic nephropathy (HN) affects many individuals with hyperuricemia, yet its molecular mechanisms are not fully understood, and effective treatments are lacking. Methods: In vitro, human tubular epithelial cells (HK-2) were exposed to uric acid for 36 hours, followed by transfection with microRNA mimic or FIH-1 siRNA. In vivo, HN was induced in mice using potassium oxonate (PO) and adenine (Ad) for two weeks. miR-295 mimic or anti-miR-295 was administered via tail vein injection, and mice were sacrificed for analysis. Results: We demonstrated a significant increase of miR-295 in renal tubular cells in HN mice. Hyperuricemia led to the activation of hypoxia inducible factor-1α (HIF-1α), and inhibition of HIF-1α by YC-1 (a HIF-1α inhibitor) prevented the increase of miR-295. ChIP assay further verified HIF-1α binding to the miR-295 gene promoter directly. Functionally, Inhibition of miR-295 led to increased cell death and tubulointerstitial fibrosis in HN mice, whereas supplementation of miR-295 mimic had kidney protective effects in this model. miR-295 suppressed the expression of factor inhibiting hypoxia-inducible factor-1 (FIH-1) in both in vitro and in vivo models of HN. Luciferase microRNA target reporter assay further verified FIH-1 as a direct target of miR-295.In addition, knockdown of FIH-1 inhibits tubular cell apoptosis and profibrotic cytokines production in HK2 cells during uric acid treatment. Conclusions: This study reveals a HIF-1α/miR-295/FIH-1 positive feedback loop that regulates tubular damage and fibrosis in HN. Plain Language Summary This study explores the molecular mechanisms of hyperuricemic nephropathy (HN), a kidney condition linked to high uric acid levels. Researchers found that in mice with HN, the microRNA miR-295 increased in kidney cells. The study identified a feedback loop involving miR-295, HIF-1α, and FIH-1, where HIF-1α activates miR-295, which then suppresses FIH-1. Inhibition of miR-295 led to increased cell death and fibrosis, while supplementation with miR-295 mimic had protective effects against kidney damage. Inhibiting HIF-1α prevented miR-295 increase. These findings suggest potential therapeutic targets for treating HN by modulating this molecular pathway. Text is machine generated and may contain inaccuracies. FAQ
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