Mitochondrial iron regulation as an emerging target in ischemia/reperfusion injury during kidney transplantation.

The injury caused by ischemia and subsequent reperfusion (I/R) is inevitable during kidney transplantation and its current management remains unsatisfactory. Iron is considered to play a remarkable pathologic role in the initiation or progression of tissue damage induced by I/R, whereas the effects of iron-related therapy remain controversial owing to the complicated nature of iron's involvement in multiple biological processes. A significant portion of the cellular iron is located in the mitochondria, which exerts a central role in the development and progression of I/R injury. Recent studies of iron regulation associated with mitochondrial function represents a unique opportunity to improve our knowledge on the pathophysiology of I/R injury. However, the molecular mechanisms linking mitochondria to the iron homeostasis remain unclear. In this review, we provide a comprehensive analysis of the alterations to iron metabolism in I/R injury during kidney transplantation, analyze the current understanding of mitochondrial regulation of iron homeostasis and discussed its potential application in I/R injury. The elucidation of regulatory mechanisms regulating mitochondrial iron homeostasis will offer valuable insights into potential therapeutic targets for alleviating I/R injury with the ultimate aim of improving kidney graft outcomes, with potential implications that could also extend to acute kidney injury or other I/R injuries.

The N6-methyladenosine writer WTAP contributes to the induction of immune tolerance post kidney transplantation by targeting regulatory T cells.

N6-methyladenosine (m6A) modification is involved in diverse immunoregulation, while the relationship between m6A modification and immune tolerance post kidney transplantation remains unclear. Expression of Wilms tumor 1-associating protein (WTAP), an m6A writer, was firstly detected in tolerant kidney transplant recipients (TOL). Then the role of WTAP on regulatory T (Treg) cell differentiation and function in CD4+ T cells from kidney transplant recipients with immune rejection (IR) was investigated. The potential target of WTAP and effect of WTAP on immune tolerance in vivo were subsequently verified. WTAP was upregulated in CD4+ T cells of TOL and positively correlated with Treg cell proportion. In vitro, WTAP overexpression promoted Treg cell differentiation and enhanced Treg cell-mediated suppression toward naïve T cells. Forkhead box other 1 (Foxo1) was identified as a target of WTAP. WTAP enhanced m6A modification of Foxo1 mRNA in coding sequence (CDS) region, leading to up-regulation of Foxo1. Overexpression of m6A demethylase removed the effect of WTAP overexpression, while Foxo1 overexpression reversed these effects. WTAP overexpression alleviated allograft rejection in model mice, as evidenced by reduced inflammatory response and increased Treg population. Our study suggests that WTAP plays a positive role in induction of immune tolerance post kidney transplant by promoting Treg cell differentiation and function.