Hsp70 promotes maturation of uromodulin mutants that cause familial juvenile hyperuricemic nephropathy and suppresses cellular damage
Hsp70 promotes maturation of uromodulin mutants that cause familial juvenile hyperuricemic nephropathy and suppresses cellular damage
复制标题
Hsp70促进导致家族性青少年高尿酸血症肾病的尿调节蛋白突变体的成熟并抑制细胞损伤
DOI：
10.1007/s10157-022-02196-y
复制
发表时间：
2022
影响因子：
2.3
通讯作者：
Hisatome Ichiro
中科院分区：
文献类型：
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作者：
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
家族性少年高尿酸血症肾病（FJHN）是由umod突变引起的常染色体显性遗传病。本实验研究了Hsp70基因表达和药理诱导对突变体C112Y和C217G的影响。方法在HEK293细胞中表达野生型（WT）、C112Y和C217G，采用western blot和流式细胞术研究其成熟和细胞损伤情况。结果膜联蛋白V染色和流式细胞术检测，C112Y和C217G的表达增加了促凋亡蛋白，降低了抗凋亡蛋白，诱导细胞凋亡。过表达Hsp70或给药Hsp70诱导剂香叶酮（GGA）可促进突变蛋白成熟，增加其分泌形式，使促凋亡和抗凋亡蛋白水平正常化，并抑制凋亡。结论Hsp70促进了C112Y和C217G的成熟，减少了细胞凋亡，提示Hsp70的诱导可能对FJHN有一定的治疗价值。
BackgroundFamilial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations inUMOD. Here we studied effects of genetic expression and pharmacological induction of Hsp70 on theUMODmutants C112Y and C217G.MethodsWe expressed wild type (WT), C112Y and C217G in HEK293 cells and studied their maturation and cellular damage using western blot and flow cytometry.ResultsExpression 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.ConclusionThese 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.