Salt suppresses IFN\u03b3 inducible chemokines through the IFN\u03b3-JAK1-STAT1 signaling pathway in proximal tubular cells

Yohei Arai,Kenichi Asano,Mayumi Oda,Daiei Takahashi,Eisei Sohara,Masato Tanaka,Minoru S H Ko,Shigeru B H Ko,Shinichi Uchida,Naohiro Nomura,Shintaro Mandai,Tatemitsu Rai

doi:10.1038/srep46580

Abstract

The mechanisms of immunoactivation by salt are now becoming clearer. However, those of immunosuppression remain unknown. Since clinical evidence indicates that salt protects proximal tubules from injury, we investigated mechanisms responsible for salt causing immunosuppression in proximal tubules. We focused on cytokine-related gene expression profiles in kidneys of mice fed a high salt diet using microarray analysis and found that both an interferon gamma (IFNγ) inducible chemokine, chemokine (C-X-C motif) ligand 9 (CXCL9), and receptor, CXCR3, were suppressed. We further revealed that a high salt concentration suppressed IFNγ inducible chemokines in HK2 proximal tubular cells. Finally, we demonstrated that a high salt concentration decreased IFNGR1 expression in the basolateral membrane of HK2 cells, leading to decreased phosphorylation of activation sites of Janus kinase 1 (JAK1) and Signal Transducers and Activator of Transcription 1 (STAT1), activators of chemokines. JAK inhibitor canceled the effect of a high salt concentration on STAT1 and chemokines, indicating that the JAK1-STAT1 signaling pathway is essential for this mechanism. In conclusion, a high salt concentration suppresses IFNγ-JAK1-STAT1 signaling pathways and chemokine expressions in proximal tubules. This finding may explain how salt ameliorates proximal tubular injury and offer a new insight into the linkage between salt and immunity.

Highlights

The mechanisms of immunoactivation by salt are becoming clearer
We further revealed that a high salt concentration suppressed the expressions of these chemokines in proximal tubules using HK2 cells, indicating the direct effect of salt on the suppression of chemokines
We demonstrated that a high salt concentration decreased IFNGR1 expression in the basolateral membrane of proximal tubular cells, leading to a decreased phosphorylation of activation sites of Janus kinase 1 (JAK1) and Signal Transducers and Activator of Transcription 1 (STAT1), the up-stream activators of the chemokines

Summary

Introduction

The mechanisms of immunoactivation by salt are becoming clearer. those of immunosuppression remain unknown. A high salt concentration suppresses IFNγ-JAK1-STAT1 signaling pathways and chemokine expressions in proximal tubules. This finding may explain how salt ameliorates proximal tubular injury and offer a new insight into the linkage between salt and immunity. Saline hydration therapy is the clinical cornerstone for the prevention of contrast-induced nephropathy and cisplatin-induced nephrotoxicity[10,11] These past studies differ in the type of fluid used for hydration, thereby revealing that hydration using a higher salt concentration, regardless of fluid osmolality, has a greater protective effect. We found that interferon gamma (IFNγ)inducible chemokines were suppressed by high salt conditions using microarray analysis, and demonstrated that Janus kinase 1 (JAK1)-Signal Transducers www.nature.com/scientificreports/. Activator of Transcription 1 (STAT1) signaling pathways play a key role in salt-induced suppression of the chemokines

Methods

Results

Conclusion