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Inhibition of MAFB and PI3K/AKT Signaling for Hereditary FSGS with Multicentric Carpotarsal Osteolysis
Toshiaki Usui1, Shun Ishibashi1,2, Ryojiro Tanaka3
1Department of Nephrology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
Key Points:
Multicentric carpotarsal osteolysis, a rare disorder, causes progressive osteolysis and kidney failure because of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene mutations. A genome-edited mouse model carrying the multicentric carpotarsal osteolysis mutation was used to obtain a deeper understanding of this rare disease. Targeting MAFB/IGF-1/PI3K/AKT signaling may provide new treatments for multicentric carpotarsal osteolysis-related nephropathy.
Background:
Multicentric carpotarsal osteolysis (MCTO) is a rare condition characterized by progressive osteolysis and often kidney failure. It is caused by autosomal dominant mutations in the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ).
Methods:
Given the absence of efficacious therapeutic interventions for MCTO and the obscurity of its pathophysiologic mechanisms, we used mice with the MCTO mutation ( MafbMCTO/MCTO mice) to explore the role of MAFB.
Results:
MafbMCTO/MCTO mice displayed FSGS, mirroring the manifestations seen in patients with MCTO. These mice showed that the MCTO mutation leads to the accumulation of MAFB protein. Heterozygous MafbMCTO/- mice, generated by crossbreeding to reduce MAFB levels, neither exhibited albuminuria nor showed any histologic abnormalities in the kidney, suggesting that excess MAFB was detrimental. We subsequently conducted RNA-seq on the glomeruli from MafbMCTO/MCTO mice and detected pronounced upregulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway through IGF-1. Given that receptor tyrosine kinases activate PI3K/AKT, we treated MafbMCTO/MCTO mice with the inhibitor imatinib. This led to a significant decline in urinary albumin levels compared with the control group.
Conclusions:
Our findings demonstrate that the MCTO mutation resulted in MAFB protein accumulation and led to the development of FSGS in mice.
Insights
Multicentric carpotarsal osteolysis (MCTO) is linked to MAFB gene mutations. Research shows excess MAFB protein causes kidney damage, suggesting a new therapeutic target for this rare disease.
Area of Science:
- Genetics and Molecular Biology
- Nephrology
- Rare Diseases
Background:
- Multicentric carpotarsal osteolysis (MCTO) is a rare genetic disorder.
- Characterized by bone loss and kidney failure.
- Caused by mutations in the MAFB gene.
Purpose of the Study:
- Investigate the role of MAFB in MCTO pathogenesis.
- Explore potential therapeutic targets for MCTO-associated nephropathy.
Main Methods:
- Utilized mice with the MCTO mutation (MafbMCTO/MCTO mice).
- Performed RNA sequencing on kidney glomeruli.
- Administered imatinib, a PI3K/AKT inhibitor, to treated mice.
Main Results:
- MafbMCTO/MCTO mice developed focal segmental glomerulosclerosis (FSGS), similar to human patients.
- MAFB protein accumulation was observed in affected mice.
- Excess MAFB proved detrimental; reducing MAFB levels ameliorated kidney abnormalities.
- The PI3K/AKT pathway was upregulated in affected glomeruli.
- Imatinib treatment significantly reduced albuminuria in MafbMCTO/MCTO mice.
Conclusions:
- MCTO mutations lead to MAFB protein accumulation and FSGS development.
- The MAFB-PI3K/AKT signaling pathway is crucial in MCTO-associated kidney disease.
- Targeting this pathway may offer a therapeutic strategy for MCTO.
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