Cover image of microscopy and Microanalysis

Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy

Abstract
  • Pathogenic INF2 mutations disrupt an interaction of INF2 with dynein light chain 1, a key dynein component. 
  • INF2 mutations enhance dynein-mediated trafficking of nephrin to proteolytic pathways, diminishing its recycling required for maintaining slit diaphragm integrity. 
  • The recognition that dysregulated dynein-mediated transport of nephrin in R218Q knockin podocytes opens an avenue for developing targeted therapy for INF2-mediated FSGS.

AMPK-SP1–Guided Dynein Expression Represents a New Energy-Responsive Mechanism and Therapeutic Target for Diabetic Nephropathy

paper2
  • AMP kinase senses diabetic stresses in podocytes, subsequently upregulates specificity protein 1–mediated dynein expression and promotes podocyte injury.
  • Pharmaceutical restoration of dynein expression by targeting specificity protein 1 represents an innovative therapeutic strategy for diabetic nephropathy.

Dynein-Mediated Trafficking, a New Mechanism of Diabetic Podocytopathy

Abstract
  • The expression of dynein is increased in human and rodent models of diabetic nephropathy (DN), eliciting a new dynein-driven pathogenesis.
  • Uncontrolled dynein impairs the molecular sieve of kidney by remodeling the postendocytic triage and homeostasis of nephrin.
  • The delineation of the dynein-driven pathogenesis promises a broad spectrum of new therapeutic targets for human DN.

Diabetes Activates Dynein Mediated trafficking and Degradation of Nephrin via AMPK/SP-1 Regulated Transcription

db activates dynein mediated trafficking/degradation of nephrin via AMPK/SP-1
  • Hyperglycemia suppresses AMPK, which in turn disinhibits SP1-guided transcription of genes encoding dynein subunits.
  • Diabetes-upregulated dynein promotes the trafficking of nephrin from recycling to lysosomal degradation pathways, leading to the depletion of nephrin, especially at the slit diaphragm. These changes eventually result in impaired podocyte function in maintaining the glomerular filtration barrier.

Diabetic Cytopathy

Rooney F, Allamargot C, Williquett J, Sun H. A New Quantitative Metric for Precise Classification of Diabetic Podocyte Injury Using Scanning Electron Microscopy. Microsc Microanal. 2025 Nov 12;31(6):ozaf122. doi: 10.1093/mam/ozaf122. PMID: 41370191; PMCID: PMC12693405.

Williquett J, Allamargot C, Sun H. AMPK-SP1-Guided Dynein Expression Represents a New Energy-Responsive Mechanism and Therapeutic Target for Diabetic Nephropathy. Kidney360. 2024 Apr 1;5(4):538-549. doi: 10.34067/KID.0000000000000392. Epub 2024 Mar 12. PubMed PMID: 38467599; PubMed Central PMCID: PMC11093544.

Sun H, Weidner J, Allamargot C, Piper RC, Misurac J, Nester C. Dynein-Mediated Trafficking: A New Mechanism of Diabetic Podocytopathy. Kidney360. 2023 Feb 1;4(2):162-176. doi: 10.34067/KID.0006852022. Epub 2022 Dec 6. PubMed PMID: 36821608; PubMed Central PMCID: PMC10103215.

Sun H, Zheng JM, Chen S, Zeng CH, Liu ZH, Li LS. Enhanced expression of ANGPTL2 in the microvascular lesions of diabetic glomerulopathy. Nephron Exp Nephrol. 2007;105(4):e117-23. doi: 10.1159/000100493. Epub 2007 Mar 7. PubMed PMID: 17347581.

Genetic Precursors to Kidney Disease

Sun H. New kid on the block: NOS1AP is a newly recognized genetic cause of steroid-resistant nephrotic syndrome in infants. Kidney Int. 2021 Sep;100(3):496-498. doi: 10.1016/j.kint.2021.02.036. Epub 2021 Mar 5. PubMed PMID: 33684448.

Chen JY, Xiang B, Sun H, Shi W, Zhao YC, Shen J, Qi M. [Principles and practices of post testing genetic counseling in the United States]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019 Jan 10;36(1):92-98. doi: 10.3760/cma.j.issn.1003-9406.2019.01.012. PubMed PMID: 30722096.

Grgic I, Hofmeister AF, Genovese G, Bernhardy AJ, Sun H, Maarouf OH, Bijol V, Pollak MR, Humphreys BD. Discovery of new glomerular disease-relevant genes by translational profiling of podocytes in vivo. Kidney Int. 2014 Dec;86(6):1116-29. doi: 10.1038/ki.2014.204. Epub 2014 Jun 18. PubMed PMID: 24940801; PubMed Central PMCID: PMC4245460.

Huang WY, Sun H, Pan XQ, Fei L, Guo M, Zhang AH, Wu YJ, Huang SM, Chen RH. [Screening of genes involved in renal interstitial fibrosis in rats with unilateral ureteral obstruction]. Zhonghua Er Ke Za Zhi. 2003 Nov;41(11):855-6. PubMed PMID: 14728897.

Other

Wang X, Chen X, Tang F, Luo W, Fang J, Qi C, Sun H, Xiao H, Peng X, Shao J. Be aware of acute kidney injury in critically ill children with COVID-19. Pediatr Nephrol. 2021 Jan;36(1):163-169. doi: 10.1007/s00467-020-04715-z. Epub 2020 Aug 26. PubMed PMID: 32844290; PubMed Central PMCID: PMC7447530.

Huang WY, Sun H, Pan XQ, Fei L, Guo M, Bao HY, Chen RH, Jiang XY. [Effects of colchicine on synthesis and excretion of cytokines and extracellular matrix by human renal fibroblasts]. Zhonghua Er Ke Za Zhi. 2004 Jul;42(7):524-8. PubMed PMID: 15324573.

Inverted Formin 2 (INF2) Pathway

Sun H, Perez-Gill C, Schlöndorff JS, Subramanian B, Pollak MR. Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy. J Am Soc Nephrol. 2021 Feb;32(2):307-322. doi: 10.1681/ASN.2020081109. Epub 2020 Dec 22. PubMed PMID: 33443052; PubMed Central PMCID: PMC8054882.

Subramanian B, Sun H, Yan P, Charoonratana VT, Higgs HN, Wang F, Lai KV, Valenzuela DM, Brown EJ, Schlöndorff JS, Pollak MR. Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury. Kidney Int. 2016 Aug;90(2):363-372. doi: 10.1016/j.kint.2016.04.020. Epub 2016 Jun 24. PubMed PMID: 27350175; PubMed Central PMCID: PMC5363079.

Sun H, Al-Romaih KI, MacRae CA, Pollak MR. Human Kidney Disease-causing INF2 Mutations Perturb Rho/Dia Signaling in the Glomerulus. EBioMedicine. 2014 Dec;1(2-3):107-15. doi: 10.1016/j.ebiom.2014.11.009. eCollection 2014 Dec. PubMed PMID: 26086034; PubMed Central PMCID: PMC4457406.

Sun H, Schlondorff J, Higgs HN, Pollak MR. Inverted formin 2 regulates actin dynamics by antagonizing Rho/diaphanous-related formin signaling. J Am Soc Nephrol. 2013 May;24(6):917-29. doi: 10.1681/ASN.2012080834. Epub 2013 Apr 25. PubMed PMID: 23620398; PubMed Central PMCID: PMC3665394.

Barua M, Brown EJ, Charoonratana VT, Genovese G, Sun H, Pollak MR. Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int. 2013 Feb;83(2):316-22. doi: 10.1038/ki.2012.349. Epub 2012 Sep 26. PubMed PMID: 23014460; PubMed Central PMCID: PMC3647680.

Sun H, Schlondorff JS, Brown EJ, Higgs HN, Pollak MR. Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2). Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2933-8. doi: 10.1073/pnas.1017010108. Epub 2011 Jan 28. PubMed PMID: 21278336; PubMed Central PMCID: PMC3041098.

Williquett J, Perez-Gill C, Allamargot C, Rooney F, Pollak M, Sun H. Dynll1-PI31 Interaction Enhances Proteolysis via the Proteasome, Representing a Novel Therapeutic Target for INF2-Related FSGS. Kidney360. 2024 Dec 2;6(1):38–48. doi: 10.34067/KID.0000000659. Epub ahead of print. PMID: 39621430; PMCID: PMC11793186.

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