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Kidney Week

Abstract: PO0666

Dynein-Driven Pathogenesis of Diabetic Podocytopathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Author

  • Sun, Hua, The University of Iowa Stead Family Children's Hospital, Iowa City, Iowa, United States
Background

Dynein-mediated trafficking of nephrin has been recently identified as a cause of INF2-mediated podocytopathy, where de-sequestrated dynein light chain (Dynll1) by mutant INF2 activated dynein transport complex, which subsequently facilitated nephrin degradation and impared its surface recycling to maintain the glomerular filtration barrier. Transcriptome study revealed upregulated expression of Dynll1 in human diabetic nephropathy (DN), suggesting a potential dynein driven pathogenesis. This work tested the hypothesis whether diabetic stresses cause podocytopathy via dynein-mediated mistrafficking of nephrin.

Methods

The transcription of dynein components in DN was analyzed in Nephroseq and compared to normal kidney, which was validated in cultured podocytes exposed to high glucose (HG, 30 mM), using cells exposed to normal glucose (NG, 5.5 Mm) as controls. The dynein-mediated post-endocytic sorting and recycling of nephrin was examined in an in vitro antibody-mediated trafficking model, with or without interference in the dynein trafficking pathway. The dynein-mediated nephrin trafficking in human DN was evaluated by the Dynll1-nephrin colocalization in kidney biopsy specimen, using normal kidney and other human podocytopathies as controls.

Results

1. Data analysis in Nephroseq revealed a significant upregulation of Dynll1 in human DN, as compared to other dynein components, and it correlated with the decline of renal function. This upregulated expression was redemonstrated in cultured podocytes exposed to HG at mRNA and protein levels, suggesting Dynll1 is a diabetes-responsive component of dynein transport complex.

2. HG-induced podocytopathy was characterized by enhanced dynein-mediated trafficking reflected by increased recruitment of dynein components to endocytosed nephrin and impaired nephrin recycling, which could be reversed by knock-out of Dynll1 or by direct inhibition of dynein.

3. Immunohistochemistry staining revealed upregulated expression of Dynll1 with a significant colocalization with nephrin in kidney biopsy sections of human DN, as seen in dynein-driven FSGS mediated by INF2 mutations.

Conclusion

Dynein-mediated mistrafficking of slit diaphragm protein is a new mechanism by which high glucose stress causes podocytopathy, where Dynll1 plays a key role as a diabetes-reponsive component. Enhanced Dynll1-nephrin colocalization may be used as a biomarker for dynein-driven pathogenesis in human DN.

Funding

  • Other NIH Support