# Targeting dynein-mediated trafficking in diabetic podocytopathy

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $429,489

## Abstract

Project Summary
Diabetic nephropathy (DN) is the most prevalent acquired glomerular disease, affecting ~1 in 3 people with
diabetes. DN is characterized by a progressive proteinuric podocytopathy leading to 30-50% of the cases of
end stage kidney disease in the United States. Limited understanding of the pathogenic mechanism constrains
therapy to slowing the progression instead of preventing the pathogenesis of DN. Podocytes maintain the
glomerular filtration barrier by forming a molecular sieve called the slit diaphragm (SD). Mistrafficking of SD
proteins, which causes their dyshomeostasis is an early event in diabetic podocyte injury. There is a critical
need to define the early trafficking mechanisms underlying the diabetes-disturbed proteostasis in podocyte, to
identify targets that inform therapies to prevent rather than postpone the progression of DN. Our recent work
implicates a unique role of dynein as an energy-responsive motor protein complex that transduces diabetic
signals into disturbed trafficking and proteostasis in podocytes. Hyperglycemia can trigger the expression of
dynein subunits, apparently via a shared regulation by energy-responsive kinases and transcription factors
(TFs). Forceful transient overexpression of these hyperglycemia-responsive dynein subunits recapitulates the
features of diabetic podocytopathy. Our goal of this proposal is to dissect the targetable mechanisms of
dynein-mediated trafficking disturbance that compromise the function and viability of podocytes, to guide
development of therapies to prevent DN. Our central hypothesis is that dynein mediates an energy-responsive
trafficking that causes diabetic podocytopathy with dyshomeostasis of proteins important for podocyte function.
Furthermore, we posit that this pathology can be attenuated by targeting the metabolism-responsive regulators
of dynein expression or activation. The specific aims include: (1) Determine how diabetes enhances dynein
expression and activity underlying podocytopathy. By analyzing the posttranslational modifications of the TFs
and epigenetic modifications of dynein gene promoters in conjunction with ChIP and reporter gene assays, we
will test whether diabetes activates dynein expression via SP/KLF family TFs modified by energy responsive
kinases and whether dynein-mediated trafficking can be reversed by targeting the TFs and kinases. (2)
Elucidate how dynein-mediated trafficking disturbs podocyte proteostasis in diabetes. Using live cell and pulse
chase-based trafficking and degradation assays, we will test whether dynein has a key role in mediating the
energy-responsive changes in protein trafficking that disturb proteostasis. (3) Remodel dynein activity to see if
it mitigates podocytopathy in diabetic mouse models. Using a mouse model with podocyte-specific
overexpression of Dctn1 (a subunit required for dynein activation), we will test whether activating dynein
directly causes podocytopathy. Using a transgenic mouse model with a po...

## Key facts

- **NIH application ID:** 10877598
- **Project number:** 1R01DK136563-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Hua Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,489
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877598

## Citation

> US National Institutes of Health, RePORTER application 10877598, Targeting dynein-mediated trafficking in diabetic podocytopathy (1R01DK136563-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877598. Licensed CC0.

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