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Nat Commun ; 14(1): 1790, 2023 03 30.
Article in English | MEDLINE | ID: mdl-36997516

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Mutations in the PKD1 gene, which encodes polycystin-1 (PC1), account for approximately 78% of cases. PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid (aa) residues of PC1 in two Pkd1-KO orthologous murine models of ADPKD suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function, and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.


Subject(s)
NADP Transhydrogenase, AB-Specific , Polycystic Kidney, Autosomal Dominant , TRPP Cation Channels , Humans , Animals , Mice , Disease Models, Animal , TRPP Cation Channels/genetics , TRPP Cation Channels/metabolism , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/pathology , Polycystic Kidney, Autosomal Dominant/therapy , Kidney/pathology , Kidney/physiology , NADP Transhydrogenase, AB-Specific/metabolism , Mitochondrial Proteins/metabolism
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