m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Abstract

The dysregulation of autophagy contributes to renal fibrosis. N6-Methyladenosine (m6A) RNA modification is a critical mediator of autophagy. Our previous studies have reported that the disorder of the PPARα/fatty acid oxidation (FAO) axis in renal tubular cells is suppressed by STAT6, which is involved in the regulation of renal fibrotic processes. Here, we found that canagliflozin significantly upregulates SQSTM1/P62, promoting PPARα-mediated FAO by inducing autophagy-dependent STAT6 degradation both in TGF-β1-treated HK2 cells and in unilateral ureteral occlusion (UUO) and ischemia–reperfusion (I/R) renal fibrosis mouse models. Knockdown of P62/SQSTM1 led to the impairment autophagic flux and the dysregulation of the STAT6/PPARα axis, which was confirmed by SQSTM1/P62cKO mice with UUO treatment along with bioinformatics analysis. Furthermore, SQSTM1/P62 deficiency in renal tubular cells inhibited canagliflozin’s effects that prevent FAO disorder in renal tubular cells and renal fibrosis. Mechanistically, the level of m6A eraser FTO, which interacted with SQSTM1 mRNA, decreased in the renal tubular cells both in vitro and in vivo after canagliflozin administration. Decrease in FTO stabilized SQSTM1 mRNA, which induced autophagosome formation. Collectively, this study uncovered a previously unrecognized function of canagliflozin in FTO in the autophagy modulation through the regulation of SQSTM1 mRNA stability in the renal tubular STAT6/PPARα/FAO axis and renal fibrosis.

Fat mass and obesity associated protein inhibits neuronal ferroptosis via the FYN/Drp1 axis and alleviate cerebral ischemia/reperfusion injury

“… 30 As a demethylase, FTO is noted to suppress m6A modification of proteins to afflict their stability. 43 , 44 Our data proved that FYN was upregulated after tMCAO/R treatment and FTO overexpression reduced FYN expression by decreasing FYN mRNA m6A modification. Considering that FYN may regulate the process of cerebral I/R, 14 we also designed related experiments to ascertain the specific effects of FYN on cerebral I/R injury.…”

“…19,42 Our experiments unveiled reduced Fe 2+ and 4HNE contents and enhanced GPX4 levels to afflict their stability. 43,44 Our data proved that FYN was upregulated after tMCAO/R treatment and FTO overexpression reduced FYN expression by decreasing FYN mRNA m6A modification.…”

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity

“…Large quantities of researches have confirmed the substantial accumulation of triglycerides and saturated free fatty acids in CKD, both of which contribute to organelle structural damage, oxidative stress, inflammatory responses, and cell death. Various pharmacological interventions, such as lipid-lowering drugs of fluvastatin 60 , PPARα agonist fenofibrate 61 , and the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin 62 , could greatly attenuate lipid-induced kidney injury and fibrosis. In contrast, MAGL, being an endogenously well-expressed component in the kidneys, presents a significant advantage compared to those small compounds.…”

Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side

“…This effect mainly depends on Akt activation as well as reduced uptake of cisplatin in the kidneys. Moreover, canagliflozin (20 mg/kg/day) was effective in providing renal protection in unilateral ureteral occlusion and ischemiareperfusion renal fibrosis mouse models [43]. In rats with membranous nephropathy, treatment with canagliflozin (10 mg/kg/day) for eight weeks decreased proteinuria and improved the hyperplasia of glomerular mesangial cells and stroma, and the thickening of the basement membrane and spiky structure.…”

“…-Nephroprotective effect by Akt activation, reduced uptake of cisplatin in the kidneys. [42] -Mice with unilateral ureteral occlusion and ischemia-reperfusion renal fibrosis -Renal protection [43] -Rats with membranous nephropathy -Decreased proteinuria and improved the hyperplasia of glomerular mesangial cells and stroma, the thickening of basement membrane and spiky structure.…”