TY - JOUR
T1 - Unilateral ureteral obstruction induces DNA repair by APE1
AU - Aamann, Maria Diget
AU - Norregaard, Rikke
AU - Kristensen, Marie Louise V
AU - Stevnsner, Tinna
AU - Frøkiær, Jørgen
N1 - Copyright © 2014, American Journal of Physiology - Renal Physiology.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - Ureteral obstruction is associated with oxidative stress and the development of fibrosis of the kidney parenchyma. Apurinic/apyrimidinic endonuclease (APE1) is an essential DNA repair enzyme for repair of oxidative DNA lesions and regulates several transcription factors. The aim of the present study was to investigate whether APE1 is regulated by acute (24 h) and chronic (7 days) unilateral ureteral obstruction (UUO). APE1 was expressed in essentially all kidney cells with the strongest expression in proximal tubuli. After 24 h of UUO, APE1 mRNA was induced in the cortex, inner stripe of the outer medulla (ISOM), and inner medulla (IM). In contrast, the APE1 protein level was not regulated in the IM and ISOM and only slightly increased in the cortex. APE1 DNA repair activity was not significantly changed. A different pattern of regulation was observed after 7 days of UUO, with an increase of the APE1 mRNA level in the cortex but not in the ISOM and IM. The APE1 protein level in the cortex, ISOM, and IM increased significantly. Importantly, we observed a significant increase in APE1 DNA repair activity in the cortex and IM. To confirm our model, we investigated heme oxygenase-1, collagen type I, fibronectin I, and α-smooth muscle actin levels. In vitro, we found the transcriptional regulatory activity of APE1 to be involved in the upregulation of the profibrotic factor connective tissue growth factor. In summary, APE1 is regulated at different levels after acute and chronic UUO. Thus, our results suggest that DNA repair activity is regulated in response to progressive (7 days) obstruction and that APE1 potentially could play a role in the development of fibrosis in kidney disease.
AB - Ureteral obstruction is associated with oxidative stress and the development of fibrosis of the kidney parenchyma. Apurinic/apyrimidinic endonuclease (APE1) is an essential DNA repair enzyme for repair of oxidative DNA lesions and regulates several transcription factors. The aim of the present study was to investigate whether APE1 is regulated by acute (24 h) and chronic (7 days) unilateral ureteral obstruction (UUO). APE1 was expressed in essentially all kidney cells with the strongest expression in proximal tubuli. After 24 h of UUO, APE1 mRNA was induced in the cortex, inner stripe of the outer medulla (ISOM), and inner medulla (IM). In contrast, the APE1 protein level was not regulated in the IM and ISOM and only slightly increased in the cortex. APE1 DNA repair activity was not significantly changed. A different pattern of regulation was observed after 7 days of UUO, with an increase of the APE1 mRNA level in the cortex but not in the ISOM and IM. The APE1 protein level in the cortex, ISOM, and IM increased significantly. Importantly, we observed a significant increase in APE1 DNA repair activity in the cortex and IM. To confirm our model, we investigated heme oxygenase-1, collagen type I, fibronectin I, and α-smooth muscle actin levels. In vitro, we found the transcriptional regulatory activity of APE1 to be involved in the upregulation of the profibrotic factor connective tissue growth factor. In summary, APE1 is regulated at different levels after acute and chronic UUO. Thus, our results suggest that DNA repair activity is regulated in response to progressive (7 days) obstruction and that APE1 potentially could play a role in the development of fibrosis in kidney disease.
KW - Apurinic/apyrimidinic endonuclease I
KW - DNA repair
KW - Fibrosis
KW - Kidney
KW - Obstructive nephropathy
KW - Unilateral ureteral obstruction
UR - http://www.scopus.com/inward/record.url?scp=84983749139&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00613.2014
DO - 10.1152/ajprenal.00613.2014
M3 - Journal article
C2 - 26608791
SN - 1931-857X
VL - 310
SP - F763-F776
JO - American Journal of Physiology: Renal Physiology
JF - American Journal of Physiology: Renal Physiology
IS - 8
ER -