Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis

Abstract Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activit...

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Autores principales:	Pauliina Saurus, Tuomas A. Tolvanen, Sonja Lindfors, Sara Kuusela, Harry Holthöfer, Eero Lehtonen, Sanna Lehtonen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d18126741d1541cb94450899dbf983bc
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spelling	oai:doaj.org-article:d18126741d1541cb94450899dbf983bc2021-12-02T15:05:17ZInhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis10.1038/s41598-017-10512-w2045-2322https://doaj.org/article/d18126741d1541cb94450899dbf983bc2017-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-10512-whttps://doaj.org/toc/2045-2322Abstract Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activity of SHIP2 and production of reactive oxygen species (ROS) are increased in cultured CD2AP knockout (CD2AP−/−) mouse podocytes. Oxidative stress was also increased in CD2AP−/− mouse glomeruli in vivo. We found that puromycin aminonucleoside (PA), known to increase ROS production and apoptosis, increases SHIP2 activity and reduces CD2AP expression in cultured human podocytes. PDK1 and CDK2, central regulators of AKT, were downregulated in CD2AP−/− or PA-treated podocytes. Downregulation of PDK1 and CDK2, ROS generation and apoptosis were prevented by CD2AP overexpression in both models. Notably, inhibition of SHIP2 activity with a small molecule inhibitor AS1949490 ameliorated ROS production in CD2AP−/− podocytes, but, surprisingly, further reduced PDK1 expression and aggravated apoptosis. AKT- and ERK-mediated signalling was diminished and remained reduced after AS1949490 treatment in the absence of CD2AP. The data suggest that inhibition of the catalytic activity of SHIP2 is beneficial in reducing oxidative stress, but leads to deleterious increase in apoptosis in podocytes with reduced expression of CD2AP.Pauliina SaurusTuomas A. TolvanenSonja LindforsSara KuuselaHarry HolthöferEero LehtonenSanna LehtonenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pauliina Saurus Tuomas A. Tolvanen Sonja Lindfors Sara Kuusela Harry Holthöfer Eero Lehtonen Sanna Lehtonen Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
description	Abstract Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activity of SHIP2 and production of reactive oxygen species (ROS) are increased in cultured CD2AP knockout (CD2AP−/−) mouse podocytes. Oxidative stress was also increased in CD2AP−/− mouse glomeruli in vivo. We found that puromycin aminonucleoside (PA), known to increase ROS production and apoptosis, increases SHIP2 activity and reduces CD2AP expression in cultured human podocytes. PDK1 and CDK2, central regulators of AKT, were downregulated in CD2AP−/− or PA-treated podocytes. Downregulation of PDK1 and CDK2, ROS generation and apoptosis were prevented by CD2AP overexpression in both models. Notably, inhibition of SHIP2 activity with a small molecule inhibitor AS1949490 ameliorated ROS production in CD2AP−/− podocytes, but, surprisingly, further reduced PDK1 expression and aggravated apoptosis. AKT- and ERK-mediated signalling was diminished and remained reduced after AS1949490 treatment in the absence of CD2AP. The data suggest that inhibition of the catalytic activity of SHIP2 is beneficial in reducing oxidative stress, but leads to deleterious increase in apoptosis in podocytes with reduced expression of CD2AP.
format	article
author	Pauliina Saurus Tuomas A. Tolvanen Sonja Lindfors Sara Kuusela Harry Holthöfer Eero Lehtonen Sanna Lehtonen
author_facet	Pauliina Saurus Tuomas A. Tolvanen Sonja Lindfors Sara Kuusela Harry Holthöfer Eero Lehtonen Sanna Lehtonen
author_sort	Pauliina Saurus
title	Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
title_short	Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
title_full	Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
title_fullStr	Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
title_full_unstemmed	Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
title_sort	inhibition of ship2 in cd2ap-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d18126741d1541cb94450899dbf983bc
work_keys_str_mv	AT pauliinasaurus inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis AT tuomasatolvanen inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis AT sonjalindfors inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis AT sarakuusela inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis AT harryholthofer inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis AT eerolehtonen inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis AT sannalehtonen inhibitionofship2incd2apdeficientpodocytesamelioratesreactiveoxygenspeciesgenerationbutaggravatesapoptosis
_version_	1718388923487485952

Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis

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