Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

• Published in: European journal of immunology 2018-02, Vol.48 (2), p.330-343
• Main Authors: Loeschenberger, Beatrix, Niess, Lea, Würzner, Reinhard, Schwelberger, Hubert, Eder, Iris E., Puhr, Martin, Guenther, Julia, Troppmair, Jakob, Rudnicki, Michael, Neuwirt, Hannes
• Format: Article
• Language: English
• Subjects: Apoptosis; Calcineurin; Calcineurin inhibitors; CD46 antigen; Complement activation; Complement component C3; Complement inhibitors; Complement system; Complex formation; Extracellular signal-regulated kinase; Intracellular signalling; Kidney transplantation; Nephrotoxicity; Phosphorylation; Renal function; Suppressor of cytokine signalling 3; Transplantation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201747135

One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C‐) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C‐system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C‐factors and downregulated SOCS‐3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/‐2 was required for these regulations. Following knock‐down and overexpression of SOCS‐3, we found that SOCS‐3 inhibits ERK1/‐2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component‐depleted conditions. In vivo, increased ERK1/‐2 phosphorylation and SOCS‐3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow‐up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS‐3 inhibits CNI‐induced ERK1/‐2 signalling, thereby blunting the negative control of C‐system activation. In renal proximal tubule cells calcineurin inhibitors (CNIs) induce ERK1/‐2 intracellular signalling and down‐regulation of the ERK1/‐2 inhibitor suppressor of cytokine signalling (SOCS) ‐3. Phosphorylated ERK1/‐2 yield decreased expression of the complement system inhibitors CD46 and CD55 which finally leads to terminal complement complex (TCC) formation, cell death and nephrotoxicity.