Atgl deficiency induces podocyte apoptosis and leads to glomerular filtration barrier damage.

Abstract

Abnormal lipid metabolism, renal lipid accumulation and lipotoxicity are associated with the pathological features of glomerulopathy. However, the mechanisms by which lipid accumulation leads to the development or progression of this disease have not been fully elucidated. In this work, we have identified a role for the rate-limiting enzyme in lipolysis, adipose triglyceride lipase (ATGL; also called patatin-like phospholipase domain-containing protein 2), in renal lipid metabolism and kidney disease. ATGL-deficient (Atgl(-/-)) mice displayed albuminuria, accompanied by ectopic deposition of fat in the kidney. Magnetic resonance imaging demonstrated that the contrast agent gadopentetic acid was retained in kidney tissue, suggesting defects in the glomerular filtration barrier. Furthermore, transmission electron microscopy revealed lipid deposits in the podocyte, along with foot process fusion and morphological changes suggestive of apoptosis. Indeed, shRNA-mediated depletion of ATGL promoted podocyte apoptosis, accompanied by increased levels of intracellular reactive oxygen species (ROS) and F-actin fibre redistribution. These effects could be partially reversed by treatment with the antioxidant N-acetylcysteine. These data suggest that ATGL deficiency induces renal lipid accumulation, proteinuria and glomerular filtration barrier dysfunction and implicate increased intracellular ROS levels in inducing podocyte F-actin rearrangement, foot process fusion and apoptosis that underlie these pathological features.

ENZYMES:

Adipose triglyceride lipase, EC3.1.1.3.

• Authors: Wen Chen, Youzhao Jiang, Jian Han, Jiongyu Hu, Ting He, Tiantian Yan, Na Huang, Qiong Zhang, Hao Mei, Yong Liao, Yuesheng Huang, Bing Chen
• Journal: The FEBS journal (FEBS J) Vol. 284 Issue 7 Pg. 1070-1081 (04 2017) ISSN: 1742-4658 [Electronic] England
• PMID: 28194887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Federation of European Biochemical Societies.

Chemical References

• Actins
• Antioxidants
• RNA, Small Interfering
• Reactive Oxygen Species
• Lipase
• PNPLA2 protein, mouse
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Actins (genetics, metabolism)
• Albuminuria (diagnostic imaging, drug therapy, genetics, pathology)
• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Gene Expression
• Glomerular Filtration Rate
• Kidney Diseases (diagnostic imaging, drug therapy, genetics, pathology)
• Lipase (antagonists & inhibitors, deficiency, genetics)
• Lipid Metabolism (drug effects)
• Lipolysis (drug effects)
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Knockout
• Podocytes (drug effects, metabolism, pathology)
• RNA, Small Interfering (genetics, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)