Journal article
Dynein-Mediated Trafficking: A New Mechanism of Diabetic Podocytopathy
Kidney360, Vol.4(2), pp.162-176
02/01/2023
DOI: 10.34067/KID.0006852022
PMCID: PMC10103215
PMID: 36821608
Abstract
Background
Diabetic nephropathy (DN) is characterized by increased endocytosis and degradation of nephrin, a protein that comprises the molecular sieve of the glomerular filtration barrier. While nephrin internalization has been found activated in diabetes-stressed podocytes, the postinternalization trafficking steps that lead to the eventual depletion of nephrin and the development of DN are unclear. Our work on an inherited podocytopathy uncovered that dysregulated dynein could compromise nephrin trafficking, leading us to test whether and how dynein mediates the pathogenesis of DN.
Methods
We analyzed the transcription of dynein components in public DN databases, using the Nephroseq platform. We verified altered dynein transcription in diabetic podocytopathy by quantitative PCR. Dynein-mediated trafficking and degradation of nephrin was investigated using an in vitro nephrin trafficking model and was demonstrated in a mouse model with streptozotocin (STZ)-induced DN and in human kidney biopsy sections.
Results
Our transcription analysis revealed increased expression of dynein in human DN and diabetic mouse kidney, correlated significantly with the severity of hyperglycemia and DN. In diabetic podocytopathy, we observed that dynein-mediated postendocytic sorting of nephrin was upregulated, resulting in accelerated nephrin degradation and disrupted nephrin recycling. In hyperglycemia-stressed podocytes, Dynll1, one of the most upregulated dynein components, is required for the recruitment of dynein complex that mediates the postendocytic sorting of nephrin. This was corroborated by observing enhanced Dynll1-nephrin colocalization in podocytes of diabetic patients, as well as dynein-mediated trafficking and degradation of nephrin in STZ-induced diabetic mice with hyperglycemia. Knockdown of Dynll1 attenuated lysosomal degradation of nephrin and promoted its recycling, suggesting the essential role of Dynll1 in dynein-mediated mistrafficking.
Conclusions
Our studies show that hyperglycemia stimulates dynein-mediated trafficking of nephrin to lysosomes by inducing its expression. The decoding of dynein-driven pathogenesis of diabetic podocytopathy offers a spectrum of new dynein-related therapeutic targets for DN.
Details
- Title: Subtitle
- Dynein-Mediated Trafficking: A New Mechanism of Diabetic Podocytopathy
- Creators
- Hua Sun - University of IowaJillian Weidner - University of IowaChantal Allamargot - University of IowaRobert C Piper - University of IowaJason Misurac - University of IowaCarla Nester - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Kidney360, Vol.4(2), pp.162-176
- DOI
- 10.34067/KID.0006852022
- PMID
- 36821608
- PMCID
- PMC10103215
- NLM abbreviation
- Kidney360
- ISSN
- 2641-7650
- Grant note
- name: HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development, award: 5K12HD027748; name: The University of Iowa Stead Family Children's Hospital and the Stead Family Department of Pediatrics Research Grant Program, award: 86023539
- Language
- English
- Date published
- 02/01/2023
- Academic Unit
- Molecular Physiology and Biophysics; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Core Research Facilities; Medicine Administration; Internal Medicine
- Record Identifier
- 9984368282802771
Metrics
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