TY - JOUR
T1 - Steroid regulation
T2 - An overlooked aspect of tolerance and chronic rejection in kidney transplantation
AU - Christakoudi, Sofia
AU - Runglall, Manohursingh
AU - Mobillo, Paula
AU - Rebollo-Mesa, Irene
AU - Tsui, Tjir Li
AU - Nova-Lamperti, Estefania
AU - Norris, Sonia
AU - Kamra, Yogesh
AU - Hilton, Rachel
AU - Bhandari, Sunil
AU - Baker, Richard
AU - Berglund, David
AU - Carr, Sue
AU - Game, David
AU - Griffin, Sian
AU - Kalra, Philip A.
AU - Lewis, Robert
AU - Mark, Patrick B.
AU - Marks, Stephen D.
AU - Macphee, Iain
AU - McKane, William
AU - Mohaupt, Markus G.
AU - Pararajasingam, Ravi
AU - Kon, Sui Phin
AU - Serón, Daniel
AU - Sinha, Manish
AU - Tucker, Beatriz
AU - Viklický, Ondrej
AU - Lechler, Robert I.
AU - Lord, Graham M.
AU - Stahl, Daniel
AU - Hernandez-Fuentes, Maria P.
PY - 2018/9/15
Y1 - 2018/9/15
N2 - 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.
AB - 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.
KW - Chronic rejection
KW - Kidney
KW - Steroid conversion
KW - Steroid receptor genes
KW - Tolerance
KW - Transplantation
UR - https://www.scopus.com/pages/publications/85042348735
U2 - 10.1016/j.mce.2018.01.021
DO - 10.1016/j.mce.2018.01.021
M3 - Article
C2 - 29427591
AN - SCOPUS:85042348735
SN - 0303-7207
VL - 473
SP - 205
EP - 216
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
ER -