Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation
Kensei Taguchi, … , Samir M. Parikh, Craig R. Brooks
Kensei Taguchi, … , Samir M. Parikh, Craig R. Brooks
Published December 1, 2022
Citation Information: J Clin Invest. 2022;132(23):e158096. https://doi.org/10.1172/JCI158096.
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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 1

PTC CG1 promotes renal fibrosis in CKD.

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PTC CG1 promotes renal fibrosis in CKD. (A) CG1 expression in kidney tis...
(A) CG1 expression in kidney tissue from patients with and without kidney injury. Scale bar: 20 μm. (B) Quantification of CG1 staining of patients in A. NK, normal kidney. (C) Representative images of RNAScope for Ccng1 and Hnf4a in PTCs of control kidney and CKD models. Scale bars: 20 μm. (D) Quantification of number of Ccng1 RNA dots in Hnf4a+ PTCs. n = 10 in control kidney; n = 25 in CKD models. (E) Quantification of the percentage of CG1+ cells in kidney tubules and all other cell types. (F) Schematic diagrams of experimental CKD models with WT and CG1-KO mice. (G) Plasma BUN at weekly time points after administration of AA (5 mg/kg every other day for a week). (H) Plasma BUN at weekly time points after repeated injection with low-dose cisplatin (5 mg/kg once a week for 4 weeks). (I) Plasma BUN on days 0, 3, and 9 after UUO surgery. (J) Representative images of obstructed kidneys in WT and CG1-KO mice in the UUO model. (K) Ratio of obstructed kidney weight (KW)/body weight. WT UUO (n = 14) and CG1-KO UUO (n = 12). (L) Representative large, scanned images of picrosirius red–stained kidney sections with polarized-light microscopy. Dashed outline indicates region of interest quantified. Scale bars: 500 μm. (M) The quantification of collagen deposition area/kidney (%) from L. Control (n = 5), CKD (n = 8–10). (N) Representative images of stained kidney for α-SMA. Scale bars: 100 μm. (O) Quantitative analysis of α-SMA+ area/cortex (%). Control (n = 5), CKD (n = 8–10). Data are presented as the mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by unpaired, 2-tailed Student’s t test (B, G, H, I, and K) or 1-way ANOVA with Tukey’s post hoc test (M and O).