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R168H and V165X mutant podocin might induce different degrees of podocyte injury via different molecular mechanisms
Author(s) -
Fan Qingfeng,
Zhang Han,
Ding Jie,
Liu Shufang,
Miao Jing,
Xing Yan,
Yu Zihua,
Guan Na
Publication year - 2009
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2009.01336.x
Subject(s) - podocin , podocyte , nephrin , biology , slit diaphragm , mutant , microbiology and biotechnology , gene knockdown , apoptosis , biochemistry , kidney , endocrinology , gene , proteinuria
A lot of mutations of podocin, a key protein of podocyte slit diaphragm (SD), have been found both in hereditary and sporadic focal segmental glomeruloscleorosis (FSGS). Nevertheless, the mechanisms of podocyte injury induced by mutant podocins are still unclear. A compound heterozygous podocin mutation was identified in our FSGS patient, leading to a truncated (podocin V165X ) and a missense mutant protein (podocin R168H ), respectively. Here, it was explored whether and how both mutant podocins induce podocyte injury in the in vitro cultured podocyte cell line. Our results showed that podocin R168H induced more significant podocyte apoptosis and expression changes in more podocyte molecules than podocin V165X . Podocyte injury caused by the normal localized podocin V165X was effectively inhibited by TRPC6 knockdown. The abnormal retention of podocin R168H in endoplasmic reticulum (ER) resulted in the mis‐localizations of other critical SD molecules nephrin, CD2AP and TRPC6, and significantly up‐regulated ER stress markers Bip/grp78, p‐PERK and caspase‐12. These results implicated that podocin R168H and podocin V165X induced different degrees of podocyte injury, which might be resulted from different molecular mechanisms. Our findings provided some possible clues for further exploring the pharmacological targets to the proteinuria induced by different mutant podocins.