Spironolactone, but not enalapril, potentiates hypoxia-inducible factor-1 alpha and Ets-1 expression in newborn rat kidney.
Hypoxia is regarded as an important physiological factor that controls nephrogenesis. We investigated whether the renin-angiotensin-aldosterone system (RAAS) affects hypoxia-related target genes in developing kidneys. Newborn rat pups were treated with enalapril (30 mg/kg/d) or spironolactone (200 mg/kg/d) for 7 days. Tissue hypoxia was assessed by the uptake of a hypoxyprobe-1, pimonidazole (200 mg/kg), and the expression of hypoxia-responsive genes. In the enalapril group, hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and Ets-1 protein expression were not changed, compared to the control group. In the spironolactone group, HIF-1alpha and Ets-1 protein expression were significantly increased by immunoblots and immunohistochemistry, whereas HIF-2alpha protein expression was not changed, compared to the control group. In the enalapril group, the immunoactivity of pimonidazole was not significantly different from that of the controls. However, in the spironolactone group, pimonidazole staining demonstrated that the cortex and medulla underwent severe hypoxia. In summary, our data showed that aldosterone inhibition in the developing kidney augmented the hypoxic responses, and up-regulated the expression of key mediators of hypoxia including HIF-1alpha and Ets-1. Angiotensin II inhibition did not affect hypoxia-related alterations in the developing kidney. The components of RAAS may differentially modulate renal hypoxia and its related target genes in the developing rat kidney.
Yim
H E
HE
Department of Pediatrics, College of Medicine, Korea University, Seoul, Korea.
Kim
J H
JH
Yoo
K H
KH
Bae
I S
IS
Jang
G Y
GY
Hong
Y S
YS
Lee
J W
JW
D000818:Animals; D000831:Animals, Newborn; D004656:Enalapril / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D013148:Spironolactone / Q000494:pharmacology*
C494043:Ets1 protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050784:Proto-Oncogene Protein c-ets-1; D013148:Spironolactone; D004656:Enalapril