炎症の「ブレーキ」遺伝子の希少な変異体が、腎臓病の転帰を明らかにするのに役立つかもしれない(Rare variants of an inflammation ‘brake’ gene may help reveal outcomes of kidney disease)

2023-04-25

2023-04-24 ニューサウスウェールズ大学(UNSW)

炎症の「ブレーキ」遺伝子の変異が発見され、腎臓病や腎不全のリスクを抱える人々のための個別化治療に一歩近づいた。
UNSW Sydney、Garvan Institute of Medical Research、Westmead Hospitalの研究者は、体内の炎症を増加させるTNFAIP3の一般的な遺伝子変異が、逆説的に短期的に腎臓をダメージから守ることができることを発見しました。
“我々は、人々が炎症を調節する方法の遺伝的な違いが、腎臓の健康状態の良し悪しにつながるかどうかを調査したかった “と、論文の上席著者でUNSWの生物工学・生物科学部(BABS)の部長であるShane Grey教授は言う。
学術誌「Kidney International」に掲載されたこの研究成果は、腎臓の損傷からどの程度回復するかを判断するのに役立つと思われます。

<関連情報>

急性腎障害における細胞質ユビキチンリガーゼTNFAIP3遺伝子の変異が転写因子NF-κB活性化に与える影響について
The impact of the cytoplasmic ubiquitin ligase TNFAIP3 gene variation on transcription factor NF-κB activation in acute kidney injury

Natasha M. Rogers,Nathan Zammit,Danny Nguyen-Ngo,Yassine Souilmi,Nikita Minhas,Daniel N. Meijles,Eleanor Self,Stacey N. Walters,Joanna Warren,Daniele Cultrone,Maryam El-Rashid,Jennifer Li,Tatyana Chtanova,Philip J. O’Connell,Shane T. Grey
Kidney International Published:April 23, 2023
DOI:https://doi.org/10.1016/j.kint.2023.02.030

Nuclear factor κB (NF-κB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI) and manifests in transplanted kidneys as delayed graft function. The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- κB signaling pathway. Common population-specific TNFAIP3 coding variants that reduce A20’s enzyme function and increase NF- κB activation have been linked to heightened protective immunity and autoimmune disease, but have not been investigated in AKI. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies single nucleotide polymorphisms of F127C; namely F127C;R22Q, F127C;G281E, F127C;W448C and F127C;N449K that reduce A20’s anti-inflammatory function in an NF- κB reporter assay. To investigate the impact of TNFAIP3 hypomorphic coding variants in AKI we tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The mouse Tnfaip3 coding variant I325N increases NF- κB activation without overt inflammatory disease, providing an immune boost as I325N mice exhibit enhanced innate immunity to a bacterial challenge. Surprisingly, despite exhibiting increased intra-kidney NF- κB activation with inflammation in IRI, the kidney of I325N mice was protected. The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- κB-dependent anti-apoptotic factors BCL-2, BCL-XL, c-FLIP and A20, altering the active redox state of the kidney with a reduction of superoxide levels and the enzyme super oxide dismutase-1, and enhancing cellular protective mechanisms including increased Foxp3⁺ T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.