MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD).Tubular cell injury plays a pivotal role in renal fibrosis.Commonly, injured tubular cells exhibit significant lipid accumulation.However, the underlying mechanisms remain poorly understood.Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry.2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice.Lipid accumulation and renal fibrosis were tested.Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models.Tubular cell-specific MAGL knock-in mice were generated.Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice.Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used.Results: 2-AG was increased in the serum or kidneys from CKD patients and models.Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/β-catenin signaling.β-catenin knockout blocked 2-AG/CB2-induced fatty acid β-oxidation (FAO) deficiency and lipid accumulation.Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis.Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis.Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis.Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.