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Comprehensive Transcriptomic and m6A Epitranscriptomic Analysis Reveals Colchicine-Induced Kidney Toxicity via DNA
Kun Tian1, Jiaxin Wen1, Dongcheng Zhang1
1Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350108, China.
Abstract:
Colchicine is commonly prescribed for inflammation and gout, but its nephrotoxicity and underlying mechanisms remain incompletely understood. The objective of this research was to clarify the association between m6A methylation modifications and nephrotoxicity caused by colchicine. A significant decrease in HK2 cell viability was observed following colchicine treatment, and mRNA sequencing (mRNA-seq) revealed the differential expression of genes associated with DNA damage and autophagy. Further methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed an association between N6-methyladenosine (m6A) modifications and the expression of genes involved in DNA damage and autophagy after colchicine exposure. Molecular docking and a molecular dynamics (MD) analysis identified ZC3H13 as a potential regulator of colchicine-induced cytotoxicity in HK2. Experimental validation confirmed that colchicine induces DNA damage and autophagy in HK2 cells, with ZC3H13 playing a significant role in these processes. In conclusion, the findings suggested that colchicine-induced damage in HK2 cells is associated with changes in m6A methylation levels in target genes and the altered expression of m6A regulator.
Insights
Colchicine treatment harms kidney cells by altering N6-methyladenosine (m6A) methylation, affecting DNA damage and autophagy pathways. ZC3H13 is identified as a key regulator in colchicine-induced nephrotoxicity.
Area of Science:
- Nephrology
- Molecular Biology
- Epigenetics
Background:
- Colchicine is widely used for gout and inflammation but its kidney toxicity mechanisms are unclear.
- Understanding colchicine's impact on kidney cells is crucial for patient safety.
Purpose of the Study:
- To investigate the role of N6-methyladenosine (m6A) methylation in colchicine-induced nephrotoxicity.
- To identify molecular mechanisms underlying colchicine's damaging effects on kidney cells (HK2).
Main Methods:
- Utilized mRNA sequencing (mRNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq) to analyze gene expression and m6A modifications.
- Employed molecular docking and molecular dynamics (MD) simulations to identify potential regulators.
- Conducted experimental validation to confirm findings in HK2 cells.
Main Results:
- Colchicine treatment reduced HK2 cell viability and altered expression of genes involved in DNA damage and autophagy.
- m6A modifications were associated with the expression of these genes following colchicine exposure.
- ZC3H13 was identified as a key regulator of colchicine-induced cytotoxicity, DNA damage, and autophagy in HK2 cells.
Conclusions:
- Colchicine-induced kidney cell damage is linked to altered m6A methylation patterns in target genes.
- Changes in m6A regulators, specifically ZC3H13, play a significant role in colchicine's nephrotoxic effects.
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