Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation

Publication date: Available online 7 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Sofia Christakoudi, Manohursingh Runglall, Paula Mobillo, Irene Rebollo-Mesa, Tjir-Li Tsui, Estefania Nova-Lamperti, Sonia Norris, Yogesh Kamra, Rachel Hilton, Sunil Bhandari, Richard Baker, David Berglund, Sue Carr, David Game, Sian Griffin, Philip A. Kalra, Robert Lewis, Patrick B. Mark, Stephen D. Marks, Iain Macphee, William McKane, Markus G. Mohaupt, Ravi Pararajasingam, Sui Phin Kon, Daniel Serón, Manish Sinha, Beatriz Tucker, Ondrej Viklický, Robert I. Lechler, Graham M. Lord, Daniel Stahl, Maria P. Hernandez-Fuentes
Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.



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