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

The novel calcineurin inhibitor voclosporin has been shown to be effective in treating lupus nephritis, a common and serious complication of lupus. However, its use has been associated with acute kidney injury (AKI), a potentially life-threatening condition. The exact mechanisms by which voclosporin causes AKI are not fully understood, but research has revealed that it reduces the expression of an enzyme called indolethylamine N-methyltransferase (Inmt). This enzyme plays a crucial role in detoxifying local uremic toxins, such as indole, which can accumulate in the kidneys and cause damage. To investigate the role of Inmt in voclosporin-induced AKI, researchers used genetically engineered mice that overexpressed Inmt or had conditional knockout of the Inmt gene. The study found that Inmt overexpression protected against high-dose voclosporin-induced AKI by preserving peroxisomal and mitochondrial integrity, reducing the production of reactive oxygen species, and preventing tubular apoptosis. The researchers used a range of techniques, including RNA sequencing, histopathology, and molecular assays, to examine gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers. They also used immunofluorescence and electron microscopy to investigate cellular and structural changes. The results showed that 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. In contrast, transgenic mice treated with voclosporin had preserved peroxisomal and mitochondrial integrity, and electron microscopy revealed that the structural peroxisomal changes observed in mouse and human CNI-induced AKI specimens were reversed in high-dose voclosporin-treated transgenic mice. Overall, the study suggests that proximal tubule-specific Inmt overexpression may be a potential therapeutic strategy for preventing or mitigating AKI in patients treated with voclosporin. By promoting catalase upregulation, reducing H2O2 levels, and restoring peroxisomal function, Inmt overexpression may help to protect the kidneys from damage caused by voclosporin, and ultimately improve patient outcomes. Link: https://pubmed.ncbi.nlm.nih.gov/40397512/