Different effects of angiotensin II and catecholamine on renal cell apoptosis and proliferation in rats.
BACKGROUND
We have recently found that chronic infusion of angiotensin II (Ang II) into rats resulted in an impairment of renal function, whereas norepinephrine (NE) infusion did not. We investigated whether chronic infusion of Ang II and NE caused different degrees of renal cell apoptosis and proliferation.


METHODS
Rats were made hypertensive via continuous infusion of either Ang II or NE for up to seven days. Renal cell apoptosis and proliferation were analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique and staining with antibody against proliferating cell nuclear antigen (PCNA), respectively. In some experiments, an inducer or inhibitor of heme oxygenase-1 (HO-1) was administered to investigate the possible role of HO-1 in renal cell homeostasis.


RESULTS
Infusion of Ang II, but not NE, resulted in approximately a sevenfold increase in bax protein at seven days of infusion. The TUNEL assay revealed that Ang II infusion significantly increased the number of apoptotic cells, whereas NE infusion did not. TUNEL- and PCNA-positive cells were mainly seen in the tubulointerstitial region of Ang II-infused rats. Ang II induced increased positivity of TUNEL, and PCNA was blocked completely by losartan, but only partially by hydralazine. Induction of HO-1 reduced and inhibition of HO increased Ang II-induced cell proliferation.


CONCLUSIONS
These data suggest that Ang II plays a pivotal role in the development of renal cell proliferation and apoptosis in the setting of hypertension. The renal HO system may modulate proliferative and pro-apoptotic effects of Ang II.
Aizawa
T
T
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Ishizaka
N
N
Kurokawa
K
K
Nagai
R
R
Nakajima
H
H
Taguchi
J
J
Ohno
M
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002875:Chromosomes / Q000235:genetics; D053938:DNA Fragmentation; D004790:Enzyme Induction / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein
D000959:Antihypertensive Agents; C494828:Bax protein, rat; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; C017803:zinc protoporphyrin; D006419:Heme Oxygenase (Decyclizing); D009638:Norepinephrine