Klotho Protein Deficiency Leads to Overactivation of μ-Calpain

Hiroshi Manya, Mitsushi Inomata, Toshihiko Fujimori, Naoshi Dohmae, Yuji Sato, Koji Takio, Yo-ichi Nabeshima, Tamao Endo
2002 Journal of Biological Chemistry  
The klotho mouse is an animal model that prematurely shows phenotypes resembling human aging. Here we report that in homozygotes for the klotho mutation (kl ؊/؊ ), ␣ II -spectrin is highly cleaved, even before the occurrence of aging symptoms such as calcification and arteriosclerosis. Because ␣ II -spectrin is susceptible to proteolysis by calpain, we examined the activation of calpain in kl ؊/؊ mice. m-Calpain was not activated, but -calpain was activated at an abnormally high level, and an
more » ... igh level, and an endogenous inhibitor of calpain, calpastatin, was significantly decreased. Proteolysis of ␣ II -spectrin increased with decreasing level of Klotho protein. Similar phenomena were observed in normal aged mice. Our results indicate that the abnormal activation of calpain due to the decrease of Klotho protein leads to degradation of cytoskeletal elements such as ␣ II -spectrin. Such deterioration may trigger renal abnormalities in kl ؊/؊ mice and aged mice, but Klotho protein may suppress these processes.
doi:10.1074/jbc.m206033200 pmid:12119304 fatcat:vunys7t7kjdqrlstjh4gdcnnhi