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Updated: Jan 8, 2026
Detection of MicroRNA Expression in the Kidneys of Immunoglobulin A Nephropathic Mice
Published on: July 8, 2020
The Positive Feedback Loop of Hypoxia-Inducible Factor-1 α /miR-295/Factor Inhibiting Hypoxia-Inducible Factor-1 in
Jiachang Li1, Yuhan Ma2, Yanni Wang1
1Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China.
Insights
A novel positive feedback loop involving hypoxia-inducible factor-1α (HIF-1α), microRNA-295 (miR-295), and factor inhibiting HIF-1 (FIH-1) was identified. This loop regulates kidney damage and fibrosis in hyperuricemic nephropathy (HN).
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Hyperuricemia is a risk factor for chronic kidney disease (CKD).
- Hyperuricemic nephropathy (HN) pathogenesis remains unclear, with limited treatment options.
- Understanding HN molecular mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying tubular damage and fibrosis in hyperuricemic nephropathy (HN).
- To investigate the role of microRNA-295 (miR-295) in HN.
- To identify potential therapeutic targets for HN.
Main Methods:
- In vitro studies using human tubular epithelial cells (HK-2) exposed to uric acid.
- In vivo studies inducing HN in mice using potassium oxonate and adenine.
- Manipulation of miR-295 and factor inhibiting hypoxia-inducible factor-1 (FIH-1) levels using mimics, inhibitors, and siRNA.
- Analysis of cellular and molecular changes, including cell death, fibrosis markers, and gene expression.
Main Results:
- miR-295 expression increased in renal tubular cells of HN mice, regulated by hypoxia-inducible factor-1α (HIF-1α).
- miR-295 directly targets and suppresses FIH-1 expression.
- Inhibition of miR-295 exacerbated tubular damage and fibrosis, while miR-295 supplementation conferred protection.
- Knockdown of FIH-1 reduced uric acid-induced tubular cell apoptosis and profibrotic cytokine production.
Conclusions:
- A positive feedback loop between HIF-1α, miR-295, and FIH-1 regulates tubular injury and fibrosis in HN.
- This HIF-1α/miR-295/FIH-1 axis represents a potential therapeutic target for hyperuricemic nephropathy.
- Further research into this pathway could lead to novel treatments for HN and related kidney diseases.
Key Points:
Hypoxia-inducible factor-1 α -mediated induction of miR-295 in renal tubular cells in hyperuricemic nephropathy. This study reveals a hypoxia-inducible factor-1 α /miR-295/factor inhibiting hypoxia-inducible factor-1 positive feedback loop that regulates tubular damage and fibrosis in hyperuricemic nephropathy.
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 factor inhibiting hypoxia-inducible factor-1 (FIH-1) siRNA. In vivo , HN was induced in mice using potassium oxonate and adenine for 2 weeks. miR-295 mimic or anti-miR-295 was administered through tail vein injection, and mice were euthanized 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-1 α (HIF-1 α ), and inhibition of HIF-1 α by YC-1 (a HIF-1 α inhibitor) prevented the increase of miR-295. Chromatin immunoprecipitation assay further verified HIF-1 α 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 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-1 α /miR-295/FIH-1 positive feedback loop that regulates tubular damage and fibrosis in HN.
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