Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation
Year: 2022
Type: article
Abstract: Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and predisposes patients to chronic kidney disease (CKD) through the AKI-to-CKD transition. Studies from our laboratory and others have demonstrated that maladaptive repair of proximal tubule cells (PTCs), including induction of dedifferentiation, G2/M cell cycle arrest, senescence, and profibrotic cytokine secretion, is a key process promoting AKI-to-CKD transition, kidney fibrosis, and CKD progression. The molecular mechanisms governing maladaptive repair and the relative contribution of dedifferentiation, G2/M arrest, and senescence to CKD remain to be resolved. We identified cyclin G1 (CG1) as a factor upregulated in chronically injured and maladaptively repaired PTCs. We demonstrated that global deletion of CG1 inhibits G2/M arrest and fibrosis. Pharmacological induction of G2/M arrest in CG1-knockout mice, however, did not fully reverse the antifibrotic phenotype. Knockout of CG1 did not alter dedifferentiation and proliferation in the adaptive repair response following AKI. Instead, CG1 specifically promoted the prolonged dedifferentiation of kidney tubule epithelial cells observed in CKD. Mechanistically, CG1 promotes dedifferentiation through activation of cyclin-dependent kinase 5 (CDK5). Deletion of CDK5 in kidney tubule cells did not prevent G2/M arrest but did inhibit dedifferentiation and fibrosis. Thus, CG1 and CDK5 represent a unique pathway that regulates maladaptive, but not adaptive, dedifferentiation, suggesting they could be therapeutic targets for CKD.
DOI: 10.1172/jci158096
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Veterans Affairs, American Heart Association, Vanderbilt University, Vanderbilt University Medical Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G107554336, G1149166549, Tie2-driven vascular control in critical illness, G2532530556, G2545169934, G3001962234, G3416501184, Vanderbilt O'Brien Kidney Center, G3726302789, G3756376927, Matrix receptors in chronic kidney disease, G3865556588, Vanderbilt Mouse Metabolic Phenotyping Center, G4320917349, G4416941928, G4513176822, G5132347646, A Human Organoid Model of Polycystic Kidney Disease, Prune Belly Syndrome: Mechanisms of Filamin A Mutations, G5853943267, G6297262231, Improving the Safety of Genome Editing With Human Kidney Organoids, CDK5 regulates mitochondrial dysfunction and fibrosis progression in chronic kidney disease, G6546324823, G711058138, Cell specific delivery of novel therapies to enhance glomerular regeneration and repair, G718647164, G7220527126, Diabetes Research and Training Center, G822669931, G8410895666, G9000002043, G9000052735, G9000060478, G9000081609, G9000106052, G9000159340, G9000183637, Molecular and Cellular Basis for Digestive Diseases, Structure and Function of Integrins in the Kidney, The role of cyclin G1 and CDK5 in chronic kidney disease., Cancer Center Support Grant, Mitochondria and metabolism in kidney disease, Vanderbilt Diabetes Research Center, Core Grant in Vision Research, The Laminin Receptors in Kidney Disease
OpenAlex ID: W4310437245