TY - JOUR
T1 - Vasohibin-1 has α-tubulin detyrosinating activity in glomerular podocytes
AU - Mifune, Tomoyo
AU - Tanabe, Katsuyuki
AU - Nakashima, Yuri
AU - Tanimura, Satoshi
AU - Sugiyama, Hitoshi
AU - Sato, Yasufumi
AU - Wada, Jun
N1 - Funding Information:
We thank Prof. Richard J. Johnson (University of Colorado Denver, CO) and Dr. Michiko Shimada (Hirosaki University, Hirosaki, Japan) for providing the conditionally immortalized human podocytes and technical assistance in cell culture. This study was supported by funds from JSPS KAKENHI Grant Number JP18K08210 (2018–2020 to K.T.) and the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University (2017–2018 to K.T.).
Funding Information:
Jun Wada receives speaker honoraria from Astra Zeneca, Daiichi Sankyo, Novartis , Novo Nordisk Pharma , Tanabe Mitsubishi and receives grant support from Astellas , Baxter , Bayer , Chugai , Dainippon Sumitomo, Kyowa Kirin , Novo Nordisk Pharma , Ono, Otsuka, Tanabe Mitsubishi, and Teijin.
Funding Information:
Jun Wada receives speaker honoraria from Astra Zeneca, Daiichi Sankyo, Novartis, Novo Nordisk Pharma, Tanabe Mitsubishi and receives grant support from Astellas, Baxter, Bayer, Chugai, Dainippon Sumitomo, Kyowa Kirin, Novo Nordisk Pharma, Ono, Otsuka, Tanabe Mitsubishi, and Teijin.We thank Prof. Richard J. Johnson (University of Colorado Denver, CO) and Dr. Michiko Shimada (Hirosaki University, Hirosaki, Japan) for providing the conditionally immortalized human podocytes and technical assistance in cell culture. This study was supported by funds from JSPS KAKENHI Grant Number JP18K08210 (2018?2020 to K.T.) and the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University (2017?2018 to K.T.).
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/4/9
Y1 - 2022/4/9
N2 - Podocytes are highly specialized epithelial cells in glomeruli, with a complex morphology composed of a cell body, primary processes, and foot processes, which maintain barrier function in glomerular filtration. The microtubule-based cytoskeleton is necessary for podocyte morphology. Microtubule structure and function can be affected by post-translational modification of tubulin, including detyrosination. Recent studies have shown that vasohibin-1 (VASH1), an antiangiogenic factor, has tubulin carboxypeptidase activity that causes detyrosination of α-tubulin. We aimed to examine the role of VASH1 in regulating α-tubulin detyrosination in podocytes and the potential involvement of VASH1 deficiency in renal morphology. In normal mouse kidneys, detyrosinated α-tubulin was mainly identified in glomeruli, especially in podocytes; meanwhile, in cultured immortalized podocytes, α-tubulin detyrosination was promoted with cell differentiation. Notably, α-tubulin detyrosination in glomeruli was diminished in Vash1 homozygous knockout (Vash1−/−) mice, and knockdown of VASH1 in cultured podocytes prevented α-tubulin detyrosination. Although VASH1 deficiency-induced downregulation of detyrosination caused no remarkable glomerular lesions, urinary albuminuria excretion and glomerular volume were significantly higher in Vash1−/− mice than in wild-type mice. Furthermore, decreased glomerular nephrin expression and narrower slit diaphragms width were observed in Vash1−/− mice. Taken together, we demonstrated that α-tubulin detyrosination in podocytes was mainly regulated by VASH1 and that VASH1 deficiency-mediated decreases in α-tubulin detyrosination led to minor alterations in podocyte morphology and predisposition to albuminuria. VASH1 expression and α-tubulin detyrosination may be novel targets for maintaining glomerular filtration barrier integrity.
AB - Podocytes are highly specialized epithelial cells in glomeruli, with a complex morphology composed of a cell body, primary processes, and foot processes, which maintain barrier function in glomerular filtration. The microtubule-based cytoskeleton is necessary for podocyte morphology. Microtubule structure and function can be affected by post-translational modification of tubulin, including detyrosination. Recent studies have shown that vasohibin-1 (VASH1), an antiangiogenic factor, has tubulin carboxypeptidase activity that causes detyrosination of α-tubulin. We aimed to examine the role of VASH1 in regulating α-tubulin detyrosination in podocytes and the potential involvement of VASH1 deficiency in renal morphology. In normal mouse kidneys, detyrosinated α-tubulin was mainly identified in glomeruli, especially in podocytes; meanwhile, in cultured immortalized podocytes, α-tubulin detyrosination was promoted with cell differentiation. Notably, α-tubulin detyrosination in glomeruli was diminished in Vash1 homozygous knockout (Vash1−/−) mice, and knockdown of VASH1 in cultured podocytes prevented α-tubulin detyrosination. Although VASH1 deficiency-induced downregulation of detyrosination caused no remarkable glomerular lesions, urinary albuminuria excretion and glomerular volume were significantly higher in Vash1−/− mice than in wild-type mice. Furthermore, decreased glomerular nephrin expression and narrower slit diaphragms width were observed in Vash1−/− mice. Taken together, we demonstrated that α-tubulin detyrosination in podocytes was mainly regulated by VASH1 and that VASH1 deficiency-mediated decreases in α-tubulin detyrosination led to minor alterations in podocyte morphology and predisposition to albuminuria. VASH1 expression and α-tubulin detyrosination may be novel targets for maintaining glomerular filtration barrier integrity.
KW - Detyrosination
KW - Microtubules
KW - Podocytes
KW - Vasohibin-1
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UR - http://www.scopus.com/inward/citedby.url?scp=85124521398&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2022.02.047
DO - 10.1016/j.bbrc.2022.02.047
M3 - Article
C2 - 35180473
AN - SCOPUS:85124521398
VL - 599
SP - 93
EP - 99
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
ER -