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OxLDL promotes podocyte migration by regulating CXCL16, ADAM10 and ACTN4.

ABSTRACT: Nephrotic syndrome (NS) is one of the most common causes of chronic kidney disease in the pediatric population. Hyperlipidemia is one of the main features of NS. The present study investigated the role of CXC motif chemokine ligand 16 (CXCL16) and ADAM metallopeptidase domain 10 (ADAM10) in oxidized low?density lipoprotein (oxLDL)?stimualted podocytes and the underlying mechanisms. CXCL16 and ADAM10 expression levels in oxLDL?treated podocytes were measured via reverse transcription?quantitative PCR and western blotting. Cell migration assays were conducted to assess the migration of oxLDL?treated podocytes. CXCL16 or ADAM10 overexpression and knockdown assays were conducted. The results indicated that oxLDL stimulation increased ADAM10 and CXCL16 expression levels, and enhanced podocyte migration compared with the control group. Moreover, CXCL16 and ADAM10 overexpression significantly increased podocyte migration and the expression of actinin??4 (ACTN4) compared with the control groups. By contrast, CXCL16 and ADAM10 knockdown significantly reduced podocyte migration and the expression of ACTN4 compared with the control groups. The results suggested that oxLDL promoted podocyte migration by regulating CXCL16 and ADAM10 expression, as well as by modulating the actin cytoskeleton. Therefore, CXCL16 and ADAM10 may serve as novel therapeutic targets for primary nephrotic syndrome in children.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7411416 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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oxLDL promotes podocyte migration by regulating CXCL16, ADAM10 and ACTN4.

Chen Yuan Y Wang Zhiyi Z Li Qian Q Yu Lichun L Zhu Yanji Y Wang Jing J Sun Shuzhen S

Molecular medicine reports 20200630 3

Nephrotic syndrome (NS) is one of the most common causes of chronic kidney disease in the pediatric population. Hyperlipidemia is one of the main features of NS. The present study investigated the role of CXC motif chemokine ligand 16 (CXCL16) and ADAM metallopeptidase domain 10 (ADAM10) in oxidized low‑density lipoprotein (oxLDL)‑stimualted podocytes and the underlying mechanisms. CXCL16 and ADAM10 expression levels in oxLDL‑treated podocytes were measured via reverse transcription‑quantitative ...[more]

PMID: 32705248

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Project description:BackgroundGenetic mutations in α-actinin-4 (ACTN4)-an important actin crosslinking cytoskeletal protein that provides structural support for kidney podocytes-have been linked to proteinuric glomerulosclerosis in humans. However, the effect of post-translational modifications of ACTN4 on podocyte integrity and kidney function is not known.MethodsUsing mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation in vitro and in vivo. We conducted x-ray crystallography, F-actin binding and bundling assays, and immunofluorescence staining to evaluate F-actin alignment. Microfluidic organ-on-a-chip technology was used to assess for detachment of podocytes simultaneously exposed to fluid flow and cyclic strain. We then used CRISPR/Cas9 to generate mouse models and assessed for renal injury by measuring albuminuria and examining kidney histology. We also performed targeted mass spectrometry to determine whether high extracellular glucose or TGF-β levels increase phosphorylation of ACTN4.ResultsCompared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin in vitro. Phosphomimetic Actn4 mouse podocytes exhibited more spatially correlated F-actin alignment and a higher rate of detachment under mechanical stress. Phosphomimetic Actn4 mice developed proteinuria and glomerulosclerosis after subtotal nephrectomy. Moreover, we found that exposure to high extracellular glucose or TGF-β stimulates phosphorylation of ACTN4 at S159 in podocytes.ConclusionsThese findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease-causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.

Dataset Information

OxLDL promotes podocyte migration by regulating CXCL16, ADAM10 and ACTN4.

Publications

oxLDL promotes podocyte migration by regulating CXCL16, ADAM10 and ACTN4.

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