Dataset Information

Genetic Ablation of Calcium-independent Phospholipase A₂? Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.

ABSTRACT: Genetic ablation of calcium-independent phospholipase A₂? (iPLA₂?) in mice results in marked damage of mitochondria and enhanced autophagy in glomerular visceral epithelial cells (GECs) or podocytes. The present study addresses the role of iPLA₂? in glomerular injury. In adriamycin nephrosis, deletion of iPLA₂? exacerbated albuminuria and reduced podocyte number. Glomerular LC3-II increased and p62 decreased in adriamycin-treated iPLA₂? knockout (KO) mice, compared with treated control, in keeping with increased autophagy in KO. iPLA₂? KO GECs in culture also demonstrated increased autophagy, compared with control GECs. iPLA₂? KO GECs showed a reduced oxygen consumption rate and increased phosphorylation of AMP kinase (pAMPK), consistent with mitochondrial dysfunction. Adriamycin further stimulated pAMPK and autophagy. After co-transfection of GECs with mito-YFP (to label mitochondria) and RFP-LC3 (to label autophagosomes), or RFP-LAMP1 (to label lysosomes), there was greater colocalization of mito-YFP with RFP-LC3-II and with RFP-LAMP1 in iPLA₂? KO GECs, compared with WT, indicating enhanced mitophagy in KO. Adriamycin increased mitophagy in WT cells. Thus, iPLA₂? has a cytoprotective function in the normal glomerulus and in glomerulopathy, as deletion of iPLA₂? leads to mitochondrial damage and impaired energy homeostasis, as well as autophagy and mitophagy.

SUBMITTER: Elimam H

PROVIDER: S-EPMC6838178 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genetic Ablation of Calcium-independent Phospholipase A2γ Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.

Elimam Hanan H Papillon Joan J Guillemette Julie J Navarro-Betancourt José R JR Cybulsky Andrey V AV

Scientific reports 20191107 1

Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) in mice results in marked damage of mitochondria and enhanced autophagy in glomerular visceral epithelial cells (GECs) or podocytes. The present study addresses the role of iPLA2γ in glomerular injury. In adriamycin nephrosis, deletion of iPLA2γ exacerbated albuminuria and reduced podocyte number. Glomerular LC3-II increased and p62 decreased in adriamycin-treated iPLA2γ knoc ...[more]

PMID: 31700134

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Project description:Primary aldosteronism is characterized by excess aldosterone secretion by the adrenal gland independent of the renin-angiotensin system and accounts for ~10% of hypertensive patients. Excess aldosterone causes cardiac hypertrophy, fibrosis, inflammation, and hypertension. The molecular mechanisms that trigger the onset and progression of aldosterone-mediated cardiac injury remain incompletely understood. MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that have been implicated in multiple cardiac pathologies; however, their regulation and role in aldosterone-mediated cardiac injury and dysfunction remains mostly unknown. We previously reported that microRNA-21 (miR-21) is the most upregulated miRNA by excess aldosterone in the left ventricle in a rat experimental model of primary aldosteronism. To elucidate the role of miR-21 in aldosterone-mediated cardiac injury and dysfunction, miR-21 knockout mice and their wild-type littermates were treated with aldosterone infusion and salt in the drinking water for 2 or 8 wk. miR-21 genetic ablation exacerbated aldosterone/salt-mediated cardiac hypertrophy and cardiomyocyte cross-sectional area. Furthermore, miR-21 genetic ablation increased the cardiac expression of fibrosis and inflammation markers and fetal gene program. miR-21 genetic ablation increased aldosterone/salt-mediated cardiac dysfunction but did not affect aldosterone/salt-mediated hypertension. miR-21 target gene Sprouty 2 may be implicated in the cardiac effects of miR-21 genetic ablation. Our study shows that miR-21 genetic ablation exacerbates aldosterone/salt-mediated cardiac hypertrophy, injury, and dysfunction blood pressure independently. These results suggest that miR-21 plays a protective role in the cardiac pathology triggered by excess aldosterone. Furthermore, miR-21 supplementation may be a novel therapeutic approach to abolish or mitigate excess aldosterone-mediated cardiovascular deleterious effects in primary aldosteronism.

Dataset Information

Genetic Ablation of Calcium-independent Phospholipase A₂? Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.

Publications

Genetic Ablation of Calcium-independent Phospholipase A<sub>2</sub>γ Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.

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Dataset Information

Genetic Ablation of Calcium-independent Phospholipase A2? Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.

Publications

Genetic Ablation of Calcium-independent Phospholipase A<sub>2</sub>γ Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Genetic Ablation of Calcium-independent Phospholipase A₂? Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice.