3939 EFFECTIVENESS OF IMATINIB FOR MCTO NEPHROPATHY

Abstract Background and Aims MAFB is a podocyte-specific transcription factor. Point mutations in the MAFB transactivation domain in humans result in multicentric carpometacarpal-tarsal osteolysis (MCTO). MCTO patients show focal segmental glomerulosclerosis (FSGS) due to podocyte damage, known as MCTO nephropathy. Effective treatment for MCTO has not been found. Imatinib is a tyrosine kinase inhibitor (TKI), which inhibits PI3K-Akt pathway, and is in long-term use for the treatment of chronic myeloid leukemia. Method In order to develop a new treatment for MCTO, we generated disease model mice using the CRISPR-Cas9 system. These animals have the same genetic mutation as human MCTO patients. Albuminuria was evaluated at 4 weeks of age, and renal histological analysis was performed at 26 weeks of age. In addition, RNA-seq for isolated glomeruli of 10-week-old MCTO mice and wild-type animal was performed for genetic and pathway analysis. Results MCTO mice exhibited growth retardation, and presented albuminuria from 4 weeks of age. Foot process effacement and FSGS-like renal histological changes were shown. Nephropathy symptoms were similar to that of human MCTO patients. Interestingly, the upregulated genes in RNA-seq analysis were a group of receptor genes associated with PI3K-Akt signaling, including lpar1 and csfr1.Transesophageal administration of imatinib, a PI3K-Akt pathway inhibitor, treatment for 5 consecutive weeks decreased albuminuria and ameliorated histological renal damage. RNA-seq of isolated glomeruli of MCTO mice after imatinib treatment showed decreased expression of genes associated with TGFβ-related signaling pathways compared to the non-treated group. Recently, enhanced PI3K-Akt signaling in podocytes has been linked to several renal diseases associated with podocyte injury. In addition, lpar1 inhibition in glomeruli is known to suppress TGFβ. Imatinib suppressed PI3K-Akt signaling, which is enhanced in podocytes of MCTO mice. This may have shown a podocyte-protective effect by suppressing fibrosis-related genes such as TGFβ. Imatinib is classified as a TKI, but frequency of podocyte toxicity is lower than other TKIs. Conclusion The podocyte injury mechanism of MCTO nephropathy is associated with enhanced PI3K-Akt signaling in podocytes. Imatinib inhibits this pathway and suppresses TGFβ. Imatinib may become a therapeutic agent for MCTO nephropathy.