Inhibition of METTL3 Attenuates Renal Fibrosis by Upregulating ABCG2 m6A Modifications via IGF2BP2-Dependent Mechanisms in Hyperuricemic Nephropathy

Hyperuricemia has been linked to kidney problems including hyperuricemic nephropathy (HN), which is characterised by inflammation and fibrosis in the kidneys. HN is frequently observed in patients with chronic gout. However, the causes of HN are not fully understood and effective treatments are limited. The status of RNA m6A, expression, and location of METTL3 in the kidney was evaluated in mice with HN. The mechanism of the METTL3-associated ABCG2 downregulation was further studied in mTEC cells and a potassium oxazinate + adenine-induced mice model and adeno-associated virus 9 (AAV9)-mediated METTL3 silencing mice. Expressions of ABCG2, α-SMA, collagen-1, TGF-β1, IL-1β, IL-6, and TNF-α were analysed using real-time PCR and western blotting. Hyperuricemia led to elevated m6A levels and METTL3 expression in mouse kidneys. METTL3 was mainly located in mTEC cells. METTL3-specific inhibitor STM2457 alleviated uric acid-induced inflammatory and fibrotic responses in mTEC cells. Mechanistically, ABCG2 was identified as a target of METTL3 by RNA sequencing. The stability of ABCG2 was decreased through the binding of IGF2BP2 (insulin-like growth factor 2 binding protein 2) to its m6A-modified stop codon regions. Silencing or inhibition of METTL3 significantly reduced uric acid-induced cell injury and increased ABCG2 expression, leading to uric acid excretion. In vivo data showed that AAV9-mediated METTL3 silencing significantly alleviated renal dysfunction and fibrosis in HN mice. Our study provides the first evidence that METTL3 regulates uric acid excretion by controlling the m6A levels of ABCG2 through the binding of IGF2BP2, and inhibiting METTL3 can effectively alleviate kidney damage caused by hyperuricemia, showing potential as a therapy for HN.