There are several implications of this work. Perhaps most importantly, these studies shift focus away from G2/M arrest as a central, required cell state for the development of fibrosis and CKD, as had been concluded previously. Deletion of CG1 inhibited both G2/M arrest and fibrosis but subsequent induction of G2/M arrest did not reverse this protective phenotype, providing strong evidence that, in this context at least, proximal tubule G2/M arrest was not sufficient to drive fibrogenesis (10). Instead, proximal tubule dedifferentiation in CKD appears to be the critical profibrogenic cell state, one that is regulated by the CG1/CDK5 axis. It is likely that G2/M arrest still plays roles in CKD, perhaps acting in addition to other profibrotic pathways rather than as a necessary and sufficient state.

Another intriguing implication of Taguchi, Elias, et al. (10) that clearly needs further investigation is the suggestion that proximal tubule dedifferentiation after AKI may be fundamentally different from dedifferentiation after CKD. While both acute and chronic injuries lead to the loss of brush border and differentiation markers, which superficially resemble equivalent dedifferentiation events, neither CG1 nor CDK5 was required for successful proximal tubule repair (10). By contrast, this signaling pathway plays a critical role in driving epithelial dedifferentiation and fibrosis in CKD. Similarly, what roles, if any, do CG1 and CDK5 play in the AKI-to-CKD transition? In mild or moderate AKI, the majority of proximal tubule cells successfully proliferate and redifferentiate after injury (11), processes that this work (10) shows do not require CG1 or CDK5. But left unresolved is whether the fraction of proximal tubule cells (~5%–10%) that take on a “failed repair” or “maladaptive” cell state after AKI do so as a consequence of activation of the CG1/CDK5 pathway. It stands to reason that they may well be related, since single-nucleus RNA sequencing of AKI-to-CKD models demonstrates that this minority cell population is not arrested at G2/M. These questions also await further experimental investigation.

That profibrotic cellular dedifferentiation in CKD can be targeted therapeutically by inhibition of CDK5 not only validates the kinase as a therapeutic target in fibrosis, but also suggests that other downstream pathways could represent additional antifibrotic targets as well. The signaling pathways either upstream of CG1 or downstream of CDK5 in proximal tubules remain undefined. Mitochondrial dynamics and dysfunction are increasingly recognized to play critical roles in driving both recovery from AKI as well as the progression of CKD (12). Mitochondrial dysfunction can lead to leakage of mitochondrial DNA into the cytosol, where it activates the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway that then drives proinflammatory cytokine expression and renal fibrosis (13). In the brain, CDK5 has established roles in promoting mitochondrial fission and dysfunction and in some neuronal cell types this pathology leads to cell death (14). Given this context, it is intriguing to speculate that the CG1/CDK5 axis may link profibrotic epithelial dedifferentiation to mitochondrial dysfunction, inflammation, and fibrosis. For example, CDK5 phosphorylates the GTPase dynamin-related protein 1 (Drp1), and this phosphorylation at S616 increases Drp1 translocation to the mitochondria, accelerating fission (15, 16). Proximal tubule–specific deletion of Drp1 promotes recovery after AKI (17), suggesting that a CDK5-dependent phosphorylation of Drp1 in CKD may cause mitochondrial fission, mitochondrial dysfunction, and potentially renal inflammation and fibrosis through the STING pathway. All of these hypotheses require testing.

In summary, Taguchi, Elias, and colleagues uncouple G2/M arrest from dedifferentiation and progression of fibrosis. They implicate a CG1/CDK5 signaling axis in regulating proximal tubule dedifferentiation and fibrosis and validate these proteins as therapeutic targets in CKD (10).