cyclin-d1 and Renal-Insufficiency--Chronic

Acute and chronic kidney injuries induce increased cell cycle progression in renal tubules. While increased cell cycle progression promotes repair after acute injury, the role of ongoing tubular cell cycle progression in chronic kidney disease is unknown. Two weeks after initiation of chronic kidney disease, we blocked cell cycle progression at G1/S phase by using an FDA-approved, selective inhibitor of CDK4/6. Blocking CDK4/6 improved renal function and reduced tubular injury and fibrosis in 2 murine models of chronic kidney disease. However, selective deletion of cyclin D1, which complexes with CDK4/6 to promote cell cycle progression, paradoxically increased tubular injury. Expression quantitative trait loci (eQTLs) for CCND1 (cyclin D1) and the CDK4/6 inhibitor CDKN2B were associated with eGFR in genome-wide association studies. Consistent with the preclinical studies, reduced expression of CDKN2B correlated with lower eGFR values, and higher levels of CCND1 correlated with higher eGFR values. CDK4/6 inhibition promoted tubular cell survival, in part, through a STAT3/IL-1β pathway and was dependent upon on its effects on the cell cycle. Our data challenge the paradigm that tubular cell cycle progression is beneficial in the context of chronic kidney injury. Unlike the reparative role of cell cycle progression following acute kidney injury, these data suggest that blocking cell cycle progression by inhibiting CDK4/6, but not cyclin D1, protects against chronic kidney injury.

Topics: Animals; Cell Cycle; Cyclin D1; Cyclin-Dependent Kinase 4; Genome-Wide Association Study; Mice; Renal Insufficiency, Chronic

Proliferation and the sequence of epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), called epithelial-mesenchymal-epithelial (EME) cycling are pivotal mechanisms of kidney repair and fibrosis. Furthermore, data suggest that dedifferentiation (EMT) is a prerequisite for proliferation of tubule cells. These processes have been shown to be regulated by STAT1/3 signaling. Suppressor of cytokine signaling-3 (SOCS-3) is a negative regulator of STAT1/3 signaling. Using a transcriptomics data set of patients with proteinuric kidney diseases we found that low levels of SOCS-3 RNA were associated with high-serum creatinine values in the long-term follow-up, which suggested a role of SOCS-3, regulated signaling in progression of chronic kidney disease. This result was validated in an independent cohort of patients with proteinuric nephropathies on protein level. In addition ∼60% of STAT target genes were differentially expressed in relation to stable kidney disease patients. Using two renal cellular models and SOCS-3 knockdown by short interfering RNA we investigated SOCS-3 effects on oncostatin M-induced STAT activation, differentiation and proliferation. SOCS-3 knockdown resulted in enhanced pSTAT1/3 phosphorylation and epithelial differentiation. The latter effect was only slightly enhanced by OSM treatment. Cellular proliferation was inhibited after SOCS-3 knockdown. This effect could not be further stimulated by OSM. Effects of SOCS-3 knockdown were not enhanced by downregulation of STAT1/3, suggesting a STAT independent effect on cell cycle regulators. Indeed, knockdown and overexpression of SOCS-3 were associated with decrease and increase of cyclin D1, -E and proliferation, respectively. In summary, SOCS-3 inhibits phosphorylation of pSTAT1/3 in renal tubule cells. Additionally, we show for the first time that-in vivo-loss of SOCS-3 is associated with unfavorable prognosis. In vitro, downregulation of SOCS-3 inhibits dedifferentiation (EMT) and cellular proliferation in kidney proximal tubule cells.

Topics: Adult; Animals; Cell Growth Processes; Cell Line; Cyclin D1; Cyclin E; Down-Regulation; Female; Gene Knockdown Techniques; Humans; Immunohistochemistry; Kidney Tubules, Proximal; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Renal Insufficiency, Chronic; Reproducibility of Results; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Statistics, Nonparametric; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Swine; Tissue Array Analysis