Voclosporin Overdose-Induced Peroxisomal Structural Changes and AKI Are Prevented by Renal Indole Detoxifier, INMT.

Abstract

Voclosporin, a novel calcineurin inhibitor, is effective for treating lupus nephritis but is associated with AKI. This study identifies indolethylamine <i>N</i>-methyltransferase, an enzyme crucial for detoxifying uremic toxins in mitigating voclosporin-induced AKI. The study highlights a novel protective mechanism of indolethylamine <i>N</i>-methyltransferase, opening avenues for future research and potential therapeutic strategies. The novel calcineurin inhibitor voclosporin is effective in treating lupus nephritis but has been associated with AKI through largely unknown mechanisms. Voclosporin-induced AKI revealed that voclosporin reduces the expression of indolethylamine <i>N</i>-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins such as indole. This study investigates whether <i>Inmt</i> overexpression can protect against high-dose voclosporin-induced AKI. This study used genetically engineered mice to explore the role of Inmt in voclosporin-induced AKI. Transgenic mice overexpressing Inmt and conditional knockout mouse models were used to assess renal proximal tubule–specific Inmt function. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined through RNA sequencing, histopathology, and various molecular assays. These analyses were further complemented with immunofluorescence and electron microscopy to investigate cellular and structural changes. Human clinical specimens were also investigated. Inmt downregulation in high-dose voclosporin-induced AKI was associated with reduced peroxisome and mitochondrion numbers and function, increased production of reactive oxygen species, and increased tubular apoptosis, as observed in conditional knockout mice. However, in transgenic mice treated with voclosporin, peroxisomal and mitochondrial integrity were preserved. Notably, electron microscopy revealed that the structural peroxisomal changes observed in mouse and human calcineurin inhibitor–induced AKI specimens were reversed in high-dose voclosoprin-treated transgenic mice. Overall, proximal tubule–specific <i>Inmt</i> overexpression protects against high-dose voclosporin-induced AKI by promoting catalase upregulation, reducing H₂O₂ levels, and restoring peroxisomal function. Inmt overexpression in proximal tubules prevented high-dose voclosporin-induced structural changes and AKI.