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GDF15 Improves Renal Injury Induced by Ectopic Lipid Deposition via AMPK/SIRT1 Pathway-Mediated Autophagy
Qiang Zhang1, Xidong Yang2, Yuxuan Yang3
1Department of Pharmacology, Binzhou Medical University, Yantai 264003, China.
Objectives:
Obesity precipitates excessive lipid accumulation within the kidney, culminating in ectopic lipid deposition that compromises target organ function through lipotoxicity. Given the pivotal role of GDF15 in lipid metabolism, this study aims to determine whether GDF15 can ameliorate ectopic lipid deposition and mitigate the resulting renal injury.
Methods:
C57BL/6J mice were used to establish a high-fat diet-induced obesity model. Based on Lee's index, the mice were categorized into a diet-induced obesity group and an obesity-resistant group. Subsequently, the diet-induced obesity group received an injection of AAV-shGFRAL to knock down the GFRAL receptor.
Results:
In obesity resistant mice, ectopic lipid deposition in the kidneys was markedly reduced, accompanied by decreased expression of the renal injury marker KIM-1 and significantly elevated levels of GDF15. Modulation of the GDF15-GFRAL axis demonstrated that reduced autophagy levels led to increased lipid accumulation and exacerbated renal injury. Conversely, GDF15 activates the AMPK/SIRT1 signaling pathway to promote cellular autophagy, thereby mitigating renal damage induced by ectopic lipid deposition. Consistent with this mechanism, the suppression of autophagy results in the aggravation of renal injury caused by ectopic lipid accumulation.
Conclusions:
GDF15 ameliorates renal injury induced by ectopic lipid deposition in the kidney primarily through activation of autophagy via the AMPK/SIRT1 signaling pathway.
Insights
Growth Differentiation Factor 15 (GDF15) reduces kidney damage from excess fat. GDF15 promotes autophagy, a cellular cleaning process, to protect kidneys from lipotoxicity.
Area of Science:
- Nephrology
- Metabolic Disorders
- Molecular Biology
Background:
- Obesity causes kidney lipid accumulation and lipotoxicity.
- Growth Differentiation Factor 15 (GDF15) plays a role in lipid metabolism.
- Ectopic lipid deposition impairs kidney function.
Purpose of the Study:
- To investigate if GDF15 can reduce kidney ectopic lipid deposition.
- To determine if GDF15 mitigates obesity-induced renal injury.
Main Methods:
- A high-fat diet induced obesity in C57BL/6J mice.
- Mice were grouped into diet-induced obesity and obesity-resistant categories.
- The GFRAL receptor was knocked down using AAV-shGFRAL in obese mice.
Main Results:
- Obesity-resistant mice showed reduced kidney lipid deposition and renal injury.
- GDF15 levels were elevated in obesity-resistant mice.
- GDF15 activates the AMPK/SIRT1 pathway, promoting autophagy and reducing lipid accumulation and renal damage.
Conclusions:
- GDF15 ameliorates kidney injury caused by ectopic lipid deposition.
- This protective effect is mediated by GDF15 activating autophagy through the AMPK/SIRT1 pathway.
