Hsp70 promotes maturation of uromodulin mutants that cause familial juvenile hyperuricemic nephropathy and suppresses cellular damage

Background Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD . Here we studied effects of genetic expression and pharmacological induction of Hsp70 on the UMOD mutants C112Y and C217G. Methods We expressed wild type (WT), C112Y and C217G...

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Published in:Clinical and experimental nephrology 2022-06, Vol.26 (6), p.522-529
Main Authors: Utami, Sulistiyati Bayu, Endo, Ryo, Hamada, Toshihiro, Notsu, Tomomi, Minato, Hiroyuki, Komatsu, Koji, Nakayama, Yuji, Shirayoshi, Yasuaki, Yamamoto, Kazuhiro, Okada, Shinichi, Ninomiya, Haruaki, Otuki, Akihiro, Hisatome, Ichiro
Format: Article
Language:English
Subjects:
Annexin V
Apoptosis
Flow cytometry
Hereditary diseases
Hsp70 protein
Medicine
Medicine & Public Health
Mutants
Mutation
Nephrology
Nephropathy
Original Article
Proteins
Software
Statistical analysis
Urology
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Summary:Background Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD . Here we studied effects of genetic expression and pharmacological induction of Hsp70 on the UMOD mutants C112Y and C217G. Methods We expressed wild type (WT), C112Y and C217G in HEK293 cells and studied their maturation and cellular damage using western blot and flow cytometry. Results Expression of C112Y or C217G increased pro-apoptotic proteins, decreased anti-apoptotic proteins, and induced cellular apoptosis as examined by annexin V staining and flow cytometry. Overexpression of Hsp70 or administration of an Hsp70 inducer geranylgeranylacetone (GGA) promoted maturation of the mutant proteins, increased their secreted forms, normalized the levels of pro- and anti-apoptotic proteins and suppressed apoptosis. Conclusion These findings indicated that Hsp70 enhanced maturation of C112Y and C217G and reduced cellular apoptosis, suggesting that Hsp70 induction might be of a therapeutic value for treatment of FJHN.
ISSN:1342-1751
1437-7799
DOI:10.1007/s10157-022-02196-y