Abstract: SA-PO119
Cyclin G1-Mediated Dedifferentiation of Proximal Tubular Cells Drives Fibrosis
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Taguchi, Kensei, Vanderbilt University Medical Center/Division of Nephrology & Hpertension, Nashville, Tennessee, United States
- Elias, Bertha C., Vanderbilt University Medical Center/Division of Nephrology & Hpertension, Nashville, Tennessee, United States
- Kishi, Seiji, Kawasaki Medical School, Kurashiki, Japan
- Canaud, Guillaume, Université Paris Descartes, INSERM U845, Hopital Necker, Paris, France
- Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
- Brooks, Craig R., Vanderbilt University Medical Center/Division of Nephrology & Hpertension, Nashville, Tennessee, United States
Background
Over 13% of the world’s population have chronic kidney disease (CKD). Severe acute kidney injury can lead to chronic kidney disease (CKD) through maladaptive repair of proximal tubular cells (PTC) and cycle arrest in the G2/M transition. Recently, we identified an atypical cyclin, cyclin G1 (CG1), as a key mediator of G2/M arrest, maladaptive repair and fibrosis; however, the underlying mechanism how CG1 regulates G2/M arrest and fibrosis remains to be resolved. The aim of the current study is to ascertain whether CG1-induced dedifferentiation drives PTC profibrotic signaling and kidney fibrosis.
Methods
Protocol 1; 8-week-old male BL57Bl/6 (WT) and CG1 knockout mice (CG1KO) received unilateral ureteral obstruction (UUO). Kidneys were taken at day 9 and fibrosis was assessed by picrosirius red staining and polarized microscopy. PTC dedifferentiation was defined by upregulated kidney injury molecule1 (KIM-1) and staining and PCR for differentiation/dedifferentiation marker expression.
Protocol 2; Primary PTCs isolated from WT and CG1KO mice were treated with aristolochic acid (AA) and gene expression was analyzed by PCR and western blot.
Results
In response to UUO, kidney fibrosis was dramatically reduced in CG1KO compared with WT. Upregulation of KIM-1 in WT-UUO was ameliorated in CG1KO and markers of differentiation were preserved at both protein and mRNA levels in CG1KO. Compatible with our animal data, connective tissue growth factor (CTGF) and fibronectin were upregulated by AA treatment in WT PTC and attenuated in CG1KO PTC. Further, AA-induced cell enlargement was restored by deletion of CG1. Na-K-ATPase and AQP1 mRNA were also maintained in CG1KO PTC. Importantly, inhibition of dedifferentiation reduced levels of G2/M arrested cells, marked by phosphorylated Histone 3 (pH3), in CG1KO-UUO kidneys compared to WT-UUO.
Conclusion
Cyclin G1 drives a maladaptive dedifferentiation of proximal tubular cells after kidney injury, resulting in increased secretion of profibrotic cytokines and progression of fibrosis. Cyclin G1-induced dedifferentiation facilitates G2/M arrest and subsequent maladaptive responses. As cyclin G1 is only expressed in chronically injured cells, it represents a potential therapeutic target for prevention of kidney fibrosis.