MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity

Abstract

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.

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

“…4−6 Emerging studies have highlighted that renal tubular ELD is a common pathological feature of chronic kidney disease (CKD), which affects more than 850 million people globally and nearly one-third of the elderly, posing a serious threat to human health. 7,8 It is generally believed that the pathophysiology of renal tubular ELD is associated with maladaptive oxidative stress, excessive inflammatory responses, and aberrant lipid metabolism, but the underlying pathogenesis of renal tubular ELD is still not fully clear. 9,10 Lipogenesis and lipolysis are the main pathways involved in renal tubular lipid metabolism, where they play a crucial role in regulating the renal tubular lipid profile to maintain the normal physiological functions of the tubules.…”

“…Chronic nutrient overload, particularly high levels of dietary fat, is commonly attributed as the primary cause of imbalanced lipid metabolism. , Notably, dyslipidemia resulting from a high-fat diet (HFD) can lead to the accumulation of excessive lipids in non-adipose tissues, a condition known as ectopic lipid deposition (ELD) . Renal tubules, being energy-demanding and metabolically active, are susceptible to ELD, which can trigger lipotoxic damage to intrinsic renal tubular cells, compromising renal reabsorption and excretion. − Emerging studies have highlighted that renal tubular ELD is a common pathological feature of chronic kidney disease (CKD), which affects more than 850 million people globally and nearly one-third of the elderly, posing a serious threat to human health. , It is generally believed that the pathophysiology of renal tubular ELD is associated with maladaptive oxidative stress, excessive inflammatory responses, and aberrant lipid metabolism, but the underlying pathogenesis of renal tubular ELD is still not fully clear. , Lipogenesis and lipolysis are the main pathways involved in renal tubular lipid metabolism, where they play a crucial role in regulating the renal tubular lipid profile to maintain the normal physiological functions of the tubules . The imbalance between lipogenesis and lipolysis resulting from a HFD is proposed as a significant factor contributing to the occurrence of renal tubular ELD and subsequent renal injury.…”