Journal article
AMPK-SP1-Guided Dynein Expression Represents a New Energy-Responsive Mechanism and Therapeutic Target for Diabetic Nephropathy
Kidney360, Vol.5(4), pp.538-549
03/12/2024
DOI: 10.34067/KID.0000000000000392
PMCID: PMC11093544
PMID: 38467599
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes. Injury to podocytes, epithelial cells that form the molecular sieve of a kidney, is a preclinical feature of DN. Protein trafficking mediated by dynein, a motor protein complex, is a newly recognized pathophysiology of diabetic podocytopathy and is believed to be derived from the hyperglycemia-induced expression of subunits crucial for the transportation activity of the dynein complex. However, the mechanism underlying this transcriptional signature remains unknown.
Through promoter analysis, we identified binding sites for transcription factor SP1 as the most shared motif among hyperglycemia-responsive dynein genes. We demonstrated the essential role of AMPK-regulated SP1 in the transcription of dynein subunits and dynein-mediated trafficking in diabetic podocytopathy using ChIP quantitative PCR and live cell imaging. SP1-dependent dynein-driven pathogenesis of diabetic podocytopathy was demonstrated by pharmaceutical intervention with SP1 in a mouse model of streptozotocin (STZ)-induced diabetes.
Hyperglycemic conditions enhance SP1 binding to dynein promoters, promoted dynein expression, and enhanced dynein-mediated mistrafficking in cultured podocytes. These changes can be rescued by chemical inhibition or genetic silencing of SP1. The direct repression of AMPK, an energy sensor, replicates hyperglycemia-induced dynein expression by activating SP1. Mithramycin inhibition of SP1-directed dynein expression in STZ-induced diabetic mice protected them from developing podocytopathy and prevented DN progression.
Our work implicates AMPK-SP1-regulated dynein expression as an early mechanism that translates energy disturbances in diabetes into podocyte dysfunction. Pharmaceutical restoration of dynein expression by targeting SP1 offers a new therapeutic strategy to prevent DN.
Details
- Title: Subtitle
- AMPK-SP1-Guided Dynein Expression Represents a New Energy-Responsive Mechanism and Therapeutic Target for Diabetic Nephropathy
- Creators
- Jillian Williquett - University of IowaChantal Allamargot - University of IowaHua Sun - Carver College of Medicine, The University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Kidney360, Vol.5(4), pp.538-549
- DOI
- 10.34067/KID.0000000000000392
- PMID
- 38467599
- PMCID
- PMC11093544
- NLM abbreviation
- Kidney360
- eISSN
- 2641-7650
- Grant note
- 2K12HD027748-31 / National Institute of Child Health and Human Development CMN86023539 / Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- Language
- English
- Electronic publication date
- 03/12/2024
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Core Research Facilities
- Record Identifier
- 9984572243402771
Metrics
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