科研之友
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摘要
Genetic alterations of alpha-actinin-4 can cause podocyte injury through multiple mechanisms. Although a mechanism involving gain-of-alpha-actinin-4 function was well described and is responsible for a dominantly inherited form of human focal segmental glomerulosclerosis (FSGS), evidence supporting mechanisms involving loss-of-alpha-actinin-4 function in human glomerular diseases remains elusive. Here we show that alpha-actinin-4 deficiency occurs in multiple human primary glomerulopathies including sporadic FSGS, minimal change disease, and IgA nephropathy. Furthermore, we identify a close correlation between the levels of alpha-actinin-4 and CLP36, which form a complex in normal podocytes, in human glomerular diseases. siRNA-mediated depletion of alpha-actinin-4 in human podocytes resulted in a marked reduction of the CLP36 level. Additionally, two FSGS-associated alpha-actinin-4 mutations (R310Q and Q348R) inhibited the complex formation between alpha-actinin-4 and CLP36. Inhibition of the alpha-actinin-4-CLP36 complex, like loss of alpha-actinin-4, markedly reduced the level of CLP36 in podocytes. Finally, reduction of the CLP36 level or disruption of the alpha-actinin-4-CLP36 complex significantly inhibited RhoA activity and generation of traction force in podocytes. Our studies reveal a critical role of the alpha-actinin-4-CLP36 complex in podocytes and provide an explanation as to how alpha-actinin-4 deficiency or mutations found in human patients could contribute to podocyte defects and glomerular failure through a loss-of-function mechanism.
- 出版日期2011-9-2
