Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Osaki, Yosuke; Manolopoulou, Marika; Ivanova, Alla V.; Vartanian, Nicholas; Mignemi, Melanie Phillips; Kern, Justin L.; Chen, Shiguo; Yang, Haichun; Fogo, Agnes B.; Zhang, Mingzhi; Robinson‐Cohen, Cassianne; Gewin, Leslie

doi:10.1172/jci.insight.158754

Cited by 14 publications

(10 citation statements)

References 57 publications

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“…These discrepant data likely indicate cell type-specific control of the cell cycle and underscore our incomplete understanding of the physiologic meaning of cell cycle states. Our data extend prior observations from other model systems that transient stalling or reversible prolongation of the cell cycle in G 2 is critical for successful repair of tissue injury (8,(91)(92)(93)(94). Cell cycle slowing after the acute kidney injury phase confers protection against chronic epithelial injury (92).…”

Section: Discussionsupporting

confidence: 85%

Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry

Bock,

Dong,

et al. 2024

Sci. Adv.

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Prolonged obstruction of the ureter, which leads to injury of the kidney collecting ducts, results in permanent structural damage, while early reversal allows for repair. Cell structure is defined by the actin cytoskeleton, which is dynamically organized by small Rho guanosine triphosphatases (GTPases). In this study, we identified the Rho GTPase, Rac1, as a driver of postobstructive kidney collecting duct repair. After the relief of ureteric obstruction, Rac1 promoted actin cytoskeletal reconstitution, which was required to maintain normal mitotic morphology allowing for successful cell division. Mechanistically, Rac1 restricted excessive actomyosin activity that stabilized the negative mitotic entry kinase Wee1. This mechanism ensured mechanical G 2 -M checkpoint stability and prevented premature mitotic entry. The repair defects following injury could be rescued by direct myosin inhibition. Thus, Rac1-dependent control of the actin cytoskeleton integrates with the cell cycle to mediate kidney tubular repair by preventing dysmorphic cells from entering cell division.

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Section: Discussionsupporting

confidence: 85%

Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry

Bock,

Dong,

et al. 2024

Sci. Adv.

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“…In this study, we also made use of an in vitro model of CKD using primary PTCs treated with AA for 7 days. While no current in vitro model completely recapitulates the complexity of mammalian CKD, our group and others ha6ve demonstrated that this model can recapitulate some of the features of CKD observed in PTCs, namely dedifferentiation, G 2 /M arrest, and secretion of profibrotic cytokines ( 15 , 51 , 52 ). Therefore, we find this model useful for confirming the specific effects of genes or drugs on PTCs.…”

Section: Discussionmentioning

confidence: 82%

Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation

Taguchi¹,

Elias²,

Sugahara³

et al. 2022

Journal of Clinical Investigation

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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, G 2 /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, G 2 /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 G 2 /M arrest and fibrosis. Pharmacological induction of G 2 /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 G 2 /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.

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“…In our study, we uncover a highly novel finding that demonstrates that in the HK2 cell line, Hyper IL-6 not only promoted elevated expression of SGLT1 but also promoted proliferation of the cells ( Figure 8 , Figure 9 and Figure 10 ). Our findings are biologically relevant as the proximal tubule is particularly targeted during acute and chronic kidney injuries [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that blocking CDK4 will prevent damaged proximal tubule cells from proliferating during kidney injury. Injured proximal tubule cells promote tubulointerstitial fibrosis through production of proinflammatory and profibrotic cytokines [ 34 ]. In conclusion, blocking cell cycle progression by inhibiting CDK4 may protect against chronic kidney disease by preventing damaged proximal tubule cells from proliferating by reducing tubular injury, fibrosis and senescence [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

The Sympathetic Nervous System Regulates Sodium Glucose Co-Transporter 1 Expression in the Kidney

et al. 2023

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Hyperactivation of the sympathetic nervous system (SNS) has been demonstrated in various conditions including obesity, hypertension and type 2 diabetes. Elevated levels of the major neurotransmitter of the SNS, norepinephrine (NE), is a cardinal feature of these conditions. Increased levels of the sodium glucose cotransporter 1 (SGLT1) protein have been shown to occur in the parotid and submandibular glands of hypertensive rodents compared to normotensive controls. However, there was a need to examine SGLT1 expression in other tissues, such as the kidneys. Whether NE may directly affect SGLT1 protein expression has not yet been investigated, although such a link has been shown for sodium glucose cotransporter 2 (SGLT2). Hence, we aimed to determine (i) whether our murine model of neurogenic hypertension displays elevated renal SGLT1 expression and (ii) whether NE may directly promote elevations of SGLT1 in human proximal tubule (HK2) cells. We did indeed demonstrate that in vivo, in our mouse model of neurogenic hypertension, hyperactivation of the SNS promotes SGLT1 expression in the kidneys. In subsequent in vitro experiments in HK2 cells, we found that NE increased SGLT1 protein expression and translocation as assessed by both specific immunohistochemistry and/or a specific SGLT1 ELISA. Additionally, NE promoted a significant elevation in interleukin-6 (IL-6) levels which resulted in the promotion of SGLT1 expression and proliferation in HK2 cells. Our findings suggest that the SNS upregulates SGLT1 protein expression levels with potential adverse consequences for cardiometabolic control. SGLT1 inhibition may therefore provide a useful therapeutic target in conditions characterized by increased SNS activity, such as chronic kidney disease.

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Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Cited by 14 publications

References 57 publications

Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry

Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry

Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation

The Sympathetic Nervous System Regulates Sodium Glucose Co-Transporter 1 Expression in the Kidney

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