Comprehensive Transcriptomic and m6A Epitranscriptomic Analysis Reveals Colchicine-Induced Kidney Toxicity via DNA...

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.