DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury

Abstract

Demethylase Tet2 plays a vital role in the immune response. Acute kidney injury (AKI) initiation and maintenance phases are marked by inflammatory responses and leukocyte recruitment in endothelial and tubular cell injury processes. However, the role of Tet2 in AKI is poorly defined. Our study determined the degree of renal tissue damage associated with Tet2 gene expression levels in a cisplatin-induced AKI mice model. Tet2-knockout (KO) mice with cisplatin treatment experienced severe tubular necrosis and dilatation, inflammation, and AKI markers’ expression levels than the wild-type mice. In addition, the administration of Tet2 plasmid protected Tet2-KO mice from cisplatin-induced nephrotoxicity, but not Tet2-catalytic-dead mutant. Tet2 KO was associated with a change in metabolic pathways like retinol, arachidonic acid, linolenic acid metabolism, and PPAR signaling pathway in the cisplatin-induced mice model. Tet2 expression is also downregulated in other AKI mice models and clinical samples. Thus, our results indicate that Tet2 has a renal protective effect during AKI by regulating metabolic and inflammatory responses through the PPAR signaling pathway.

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

“…In tissue derived from CKD patients, TET1-3 levels are increased; however, their activity is decreased [ 107 ], indicating an imbalance in 5mC/5hmC. TET2 low activity is associated with worsen acute kidney damage induced by I/R [ 108 , 109 ] and cisplatin [ 110 ]; whereas TET3 low activity is associated with chronic kidney damage induced by UUO [ 111 , 112 ]; moreover, restoration of TET function ameliorates kidney injury [ 107 , 110 , 112 ] by the hydroxymethylation of different genes such as Klotho [ 107 ] and ras protein activator like 1 (RASAL) [ 111 ] promoters, which codify for renoprotective and anti-proliferative proteins, respectively. In addition, in UUO and nephrectomy models of kidney damage, the inhibition of the histone demethylase Jumonji domain containing-3 (JMJD3), another 2OGGD, worsen fibrotic lesions through enhancing TGF-β signaling [ 113 ].…”

Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis

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Serum IL-12p40: A novel biomarker for early prediction of minimal change disease relapse following glucocorticoids therapy

“…These procedures performed as previously described. ( 14 , 15 ) The primary antibodies used were as follows: anti-IL12RB1 (13287-1-AP; Proteintech) and anti-Synapotodin (sc-515842; Santa Cruz).…”