Decoupling dedifferentiation and G2/M arrest in kidney fibrosis
Benjamin D. Humphreys
Benjamin D. Humphreys
Published December 1, 2022
Citation Information: J Clin Invest. 2022;132(23):e163846. https://doi.org/10.1172/JCI163846.
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Commentary

Decoupling dedifferentiation and G2/M arrest in kidney fibrosis

Abstract

Understanding the cellular mechanisms underlying chronic kidney disease (CKD) progression is required to develop effective therapeutic approaches. In this issue of the JCI, Taguchi, Elias, et al. explore the relationship between cyclin G1 (CG1), an atypical cyclin that induces G2/M proximal tubule cell cycle arrest, and epithelial dedifferentiation during fibrogenesis. While CG1-knockout mice were protected from fibrosis and had reduced G2/M arrest, protection was unexpectedly independent of induction of G2/M arrest. Rather, CG1 drove fibrosis by regulating maladaptive dedifferentiation in a CDK5-dependent mechanism. These findings highlight the importance of maladaptive epithelial dedifferentiation in kidney fibrogenesis and identify CG1/CDK5 signaling as a therapeutic target in CKD progression.

Authors

Benjamin D. Humphreys

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Figure 1

The CG1/CDK5 pathway is involved in regulating proximal tubule dedifferentiation and fibrosis in CKD.

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The CG1/CDK5 pathway is involved in regulating proximal tubule dediffere...
Chronic kidney injury induces cells in the proximal tubule (PT) to undergo maladaptive dedifferentiation with a G2/M cell cycle–arrested phenotype. These cells also show high Sox9 and VIM expression and activation of the CG1/CDK5 pathway. Ensuing proinflammatory and profibrotic signaling results in fibrosis and decreased kidney function. Compared with WT CKD models, PTs lacking CDK5 have reduced dedifferentiation, characterized by reduced Sox9 and VIM expression. However, cells without CKD5 remain arrested in the G2/M phase of the cell cycle, similarly to WT cells. Notably, the resultant phenotype displays reduced fibrosis with CKD despite induction of G2/M cell cycle arrest (10).