Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation
Kensei Taguchi, Bertha C. Elias, Sho Sugahara, Snehal Sant, Benjamin S. Freedman, Sushrut S. Waikar, Ambra Pozzi, Roy Zent, Raymond C. Harris, Samir M. Parikh, Craig R. Brooks
Kensei Taguchi, Bertha C. Elias, Sho Sugahara, Snehal Sant, Benjamin S. Freedman, Sushrut S. Waikar, Ambra Pozzi, Roy Zent, Raymond C. Harris, Samir M. Parikh, Craig R. Brooks
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Research Article Nephrology

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

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.

Authors

Kensei Taguchi, Bertha C. Elias, Sho Sugahara, Snehal Sant, Benjamin S. Freedman, Sushrut S. Waikar, Ambra Pozzi, Roy Zent, Raymond C. Harris, Samir M. Parikh, Craig R. Brooks

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Figure 4

CG1 modulates PTC dedifferentiation and proliferation in CKD.

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CG1 modulates PTC dedifferentiation and proliferation in CKD. (A and B) ...
(A and B) Representative images of SOX9-labeled kidney sections from WT and CG1-KO mice in acute (day 7) and chronic (day 42) phases of AA. Scale bar: 20 μm (C) Corresponding quantification of the number of SOX9+ cells/kidney. Control (n = 5) and injured kidney (n = 3–6). (D) Western blot analysis of KIM-1, SOX9, and β-actin in acute phase of AA, including day 7 and day 14 after administration of AA and the corresponding quantification of SOX9/β-actin and KIM-1/β-actin. (E and F) Representative images of SOX9- and Ki-67–labeled kidney sections from WT and CG1-KO mice on day 3 and day 9 of UUO and corresponding quantification of the number of SOX9+ or Ki-67+ cells/kidney. Control (NK; n = 5) and injured kidney (n = 5–9). Scale bar: 20 μm. (G) Representative images of LTL staining in kidneys on days 0, 14, 28, and 42 following AA and corresponding quantification. Scale bar: 50 μm. (H) Western blotting analysis of YAP in whole-kidney lysates of WT and CG1-KO mice following AA. (I) Representative images of Na+/K+-ATPase– or VIM-stained kidney sections following UUO. Scale bars: 100 μm. HM, high magnification. (J) The corresponding quantification of Na+/K+-ATPase+ or VIM+ area/cortex (%). Control (n = 4–6) and injured kidney (n = 8–9). Scale bar: 100 μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA with Tukey’s post hoc test.