All of the Twos, 22—Bingo!

Abstract

is critical in embryogenesis, whereas BMP7 is critical in kidney development regulating the differentiation of metanephric mesenchymal cells required for ureteric bud branching. [11][12][13] It is tempting to speculate that BMP7 regulation of Tet3 expression and the resulting effect on the epigenome play an important role in nephrogenesis.The study by Tampe et al. 7 indicates that Rasal1 promoter hypermethylation and reduced Tet3 expression are features of renal fibrosis. BMP7 treatment resulted in normalization of Tet3 expression and consequently hydroxymethylation of the Rasal1 promoter. BMP7-mediated hydroxymethylation of the Rasal1 promoter was impaired when Tet3 expression was lost. Electrophoretic mobility shift assays confirmed binding of Tet3 to its CXXC binding motif flanking the Rasal1 CpG island promoter, further indicating the role of Tet3 in Rasal1 hydroxymethylation.Preclinical data from this study indicate that aberrant methylation or perhaps active demethylation processes catalyzed by Tet3 determine the balance between health and CKD. These findings suggest that transient therapies targeted at amplifying or restoring Tet3 activity may prove beneficial to patients with CKD. Furthermore, analysis of methylation status (e.g., using RASAL1 as a methylation biomarker) to determine the individual risk of a patient to develop fibrosis or suitability for demethylation-based therapy appears both plausible and attractive. However, further studies in larger patient cohorts are warranted to establish these targets for both diagnosis and therapy.Demethylation agents, such as 5-azacytidine, have already been described to rescue kidney fibrosis in experimental models 3 and demethylation agents are in clinical trials for treatment of cancers; however, these drugs are cytotoxic and the long-term effects of genome-wide demethylation are unknown. It therefore seems more attractive to transiently and specifically reactivate an endogenous demethylation process and thereby readdress the imbalance that results in CKD. The identification of Tet3 as a critical player in both the development and reversal of renal fibrogenesis described in the study by Tampe et al. 7 may be the first step toward achieving this attractive possibility.

Interleukin-22 Attenuated Renal Tubular Injury in Aristolochic Acid Nephropathy via Suppressing Activation of NLRP3 Inflammasome

“…Notably, there is a growing evidence demonstrating that IL-22 possesses a therapeutic potential for acute kidney injury by targeting renal tubular epithelium. Previous literatures have indicated that IL-22 efficiently ameliorated renal lesions, accelerated renal regeneration and preserved renal function in acute renal injury through downregulation of the inflammatory responses (18, 19, 23). It has also been reported that IL-22 could restrain NLRP3 inflammasome activation by facilitating the sustained generation of the IL-1 receptor antagonist (IL-Ra) (24).…”