ETA receptor blockade induces fibrosis of the clipped kidney in two-kidney-one-clip renovascular hypertensive rats.
BACKGROUND
In two kidney-one clip renovascular hypertension (2K1C), blood flow is reduced in the clipped kidney leading to ischaemia. The non-clipped kidney is characterized by increased shear stress. Circulating Ang II is elevated. All these factors are stimuli of the paracrine renal endothelin system. Indeed, we demonstrated an activation of the renal endothelin system in the 2K1C rat model.


METHODS
We analysed the effects of chronic treatment with the ETA receptor antagonist BQ-123 on blood pressure, heart rate, plasma renin activity, and on the progression of glomerulosclerosis, interstitial fibrosis and vascular remodeling in the clipped and non-clipped kidney.


RESULTS
Long-term treatment with BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group. Computer-aided image analysis revealed a markedly enhanced interstitial fibrosis of these clipped kidneys after long-term ETA blockade. The effects of ETA receptor antagonists on the non-clipped kidney were less pronounced. Neither blood pressure nor plasma renin activity were significantly altered by BQ-123 treatment.


CONCLUSIONS
The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.
Hocher
B
B
Department of Nephrology, Universitätsklinikum Charité der Humboldt Universität zu Berlin, Germany. berthold.hocher@rz.hu-berlin-de
George
I
I
Diekmann
F
F
Zart
R
R
Rebstock
J
J
Schwarz
A
A
Thöne-Reineke
C
C
Neumayer
H H
HH
Bauer
C
C
D000818:Animals; D001284:Atrophy; D003404:Creatinine / Q000097:blood; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis / Q000473:pathology; D006977:Hypertension, Renal / Q000473:pathology* / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology; D008297:Male; D009929:Organ Size; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D012083:Renin / Q000097:blood
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D003404:Creatinine; D012083:Renin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)