TY - JOUR
T1 - Inhibition of src family kinases ameliorates lps-induced acute kidney injury and mitochondrial dysfunction in mice
AU - Pak, Eun Seon
AU - Uddin, Md Jamal
AU - Ha, Hunjoo
N1 - Funding Information:
Funding: This work was funded by National Research Foundation grants (No. 2017R1D1A1B03028835 and 2020R1I1A1A01072879) and RP-Grant 2020 of Ewha Womans University, Korea. The Nox2 and Nox4 antibodies were kind gifts from Yun Soo Bae, Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, Korea.
Funding Information:
This work was funded by National Research Foundation grants (No. 2017R1D1A1B03028835 and 2020R1I1A1A01072879) and RP-Grant 2020 of Ewha Womans University, Korea. The Nox2 and Nox4 antibodies were kind gifts from Yun Soo Bae, Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, Korea.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Acute kidney injury (AKI), a critical syndrome characterized by a rapid decrease of kidney function, is a global health problem. Src family kinases (SFK) are proto-oncogenes that regulate diverse biological functions including mitochondrial function. Since mitochondrial dysfunction plays an important role in the development of AKI, and since unbalanced SFK activity causes mitochondrial dysfunction, the present study examined the role of SFK in AKI. Lipopolysaccharides (LPS) inhibited mitochondrial biogenesis and upregulated the expression of NGAL, a marker of tubular epithelial cell injury, in mouse proximal tubular epithelial (mProx) cells. These alterations were prevented by PP2, a pan SFK inhibitor. Importantly, PP2 pretreatment significantly ameliorated LPS-induced loss of kidney function and injury including inflammation and oxidative stress. The attenuation of LPS-induced AKI by PP2 was accompanied by the maintenance of mitochondrial biogenesis. LPS upregulated SFK, especially Fyn and Src, in mouse kidney as well as in mProx cells. These data suggest that Fyn and Src kinases are involved in the pathogenesis of LPS-induced AKI, and that inhibition of Fyn and Src kinases may have a potential therapeutic effect, possibly via improving mitochondrial biogenesis.
AB - Acute kidney injury (AKI), a critical syndrome characterized by a rapid decrease of kidney function, is a global health problem. Src family kinases (SFK) are proto-oncogenes that regulate diverse biological functions including mitochondrial function. Since mitochondrial dysfunction plays an important role in the development of AKI, and since unbalanced SFK activity causes mitochondrial dysfunction, the present study examined the role of SFK in AKI. Lipopolysaccharides (LPS) inhibited mitochondrial biogenesis and upregulated the expression of NGAL, a marker of tubular epithelial cell injury, in mouse proximal tubular epithelial (mProx) cells. These alterations were prevented by PP2, a pan SFK inhibitor. Importantly, PP2 pretreatment significantly ameliorated LPS-induced loss of kidney function and injury including inflammation and oxidative stress. The attenuation of LPS-induced AKI by PP2 was accompanied by the maintenance of mitochondrial biogenesis. LPS upregulated SFK, especially Fyn and Src, in mouse kidney as well as in mProx cells. These data suggest that Fyn and Src kinases are involved in the pathogenesis of LPS-induced AKI, and that inhibition of Fyn and Src kinases may have a potential therapeutic effect, possibly via improving mitochondrial biogenesis.
KW - Acute kidney injury
KW - Inflammation
KW - Mitochondrial biogenesis
KW - Oxidative stress
KW - Src family kinases inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85095794147&partnerID=8YFLogxK
U2 - 10.3390/ijms21218246
DO - 10.3390/ijms21218246
M3 - Article
C2 - 33153232
AN - SCOPUS:85095794147
SN - 1661-6596
VL - 21
SP - 1
EP - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 21
M1 - 8246
ER -