SOCS-3 is downregulated in progressive CKD patients and regulates proliferation in human renal proximal tubule cells in a STAT1/3 independent manner

Abstract

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 B60% 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.

miR‑885‑5p upregulation promotes colorectal cancer cell proliferation and migration by targeting suppressor of cytokine signaling

“…Importantly, Fujitake et al ( 33 ) reported aberrant expression of SOCS1 in patients with colorectal cancer. A previous study also demonstrated that EMT is regulated by STAT1/3 signaling, while SOCS is a negative regulator of STAT1/3 signaling ( 34 ). Thus, EMT may be negatively regulated by SOCS, which was in accordance with the present study, whereby the expression of E-cadherin decreased significantly and the expression levels of N-cadherin, vimentin and Snail increased significantly in si-SOCS + miR-885-5p inhibitor groups compared with the miR-885-5p inhibitor group alone.…”

Induction of SOCS Expression by EV71 Infection Promotes EV71 Replication

“…The critical role of SOCS3 is manifested by its binding to both JAKs and cytokine receptors, which results in the inhibition of STAT3 phosphorylation. STAT3 triggers a variety of gene expressions in response to cytokine (such as IL-6 and IL-10) and growth factor stimulation and plays a critical role in many cellular biological processes involved in anti-/proinflammatory responses, cell growth, and cell death [27,28]. However, we demonstrated that early EV71 infection quickly activated SOCS protein expression and inhibited IFN-induced STAT3 phosphorylation.…”

Suppressor of Cytokine Signaling-1 Peptidomimetic Limits Progression of Diabetic Nephropathy

“…10,11,13 In particular, SOCS1/3 expression pattern is altered in inflammatory diseases 12,18,27,28 and correlates with cardiovascular risk and progressive loss of renal function in CKD. 29,30 Our reports in diabetic patients and animals 17,31 proposed SOCS1 induction as a compensatory mechanism not sufficient to suppress JAK/STAToveractivation in renal disease. Accordingly, SOCS1 gene therapy using local and systemic delivery routes mitigates proteinuria, renal inflammation, and fibrosis in diabetic mice.…”