AI Article Synopsis
- Genetic mutations in ACTN4, crucial for kidney podocyte structure, are linked to serious kidney diseases, but the impact of its phosphorylation on podocyte function remains unclear.
- Researchers discovered that phosphorylation at serine 159 affects ACTN4's binding and bundling ability with F-actin, increasing podocyte detachment under stress and leading to kidney damage in mouse models.
- High glucose levels and TGF- stimulate this phosphorylation, suggesting that both genetic mutations and environmental factors could contribute to podocyte injury and kidney disease.
Article Abstract
Background: Genetic mutations in -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.
Methods: Using 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 and . 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- levels increase phosphorylation of ACTN4.
Results: Compared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin . 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- stimulates phosphorylation of ACTN4 at S159 in podocytes.
Conclusions: These 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351002 | PMC |
| http://dx.doi.org/10.1681/ASN.2019101032 | DOI Listing |
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