Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function.
BACKGROUND
There is growing evidence of long-term pathological consequences following renal ischemia. Endothelin (ET) receptor antagonists have proved beneficial in the treatment of ischemic acute renal failure (IARF); however, the long-term outcomes have not been assessed in this disease.


METHODS
Experimental IARF was induced in uninephrectomized female Sprague-Dawley rats (N = 8) by clamping of the renal pedicle. At 24-hours postischemia, a once-only administration of drug or vehicle was given. One ischemic group received saline only (saline ischemic), and two other ischemic groups received either SB 234551 (ETA receptor antagonist, ETA group) or SB 209670 (ETA and ETB receptor antagonist, ETA/ETB group). A uninephrectomized control group was sham operated to simulate operative conditions without ischemia and was given a once-only saline infusion (sham ischemic). All groups were sacrificed at six-months postischemia. Serum creatinine was assessed daily for one week and then every four weeks. Glomerular filtration rates (GFRs), systolic blood pressure, 24-hour urine collection, and creatinine clearance were performed just prior to sacrifice. Immunohistochemistry for monocytes and macrophages (Mo and Mphi), myofibroblasts (MF, alpha-SMA), collagen IV, and collagen III was also evaluated. Cell kinetics were studied by immunostaining for proliferating cell nuclear antigen (PCNA) and by TUNEL.


RESULTS
Urinalysis revealed significant increases in urinary protein and albumin in the ETA/ETB group when compared with all other groups. GFRs and creatinine clearance were also decreased significantly in the ETA/ETB group. Urine albumin, protein, GFR, and creatinine clearance in the ETA group, however, were not different from the sham ischemic and saline ischemic groups. Systolic blood pressure was increased in the saline ischemic group as compared with all other groups. Kidney weights were increased in all ischemic groups, but no differences were observed between the saline ischemic group and ETR antagonist-treated groups. Immunohistochemistry revealed relationships between Mo and Mphi, MF, and tubulointerstitial collagen III, where the saline ischemic and ETA/ETB groups were increased as compared with the sham ischemic and ETA groups. There was no change observed in tubulointerstitial collagen IV accumulation. The largest number of proliferating cells was demonstrated in the ETA/ETB group, whereas apoptotic cells were identified in small amounts in all groups, with the largest number being found in the saline ischemic group.


CONCLUSIONS
Renal ischemia appears to have long-term functional and pathological consequences that can be prevented by treatment with ETA receptor antagonists. Blockade of both ETA and ETB receptors, however, appears to be detrimental to long-term kidney function.
Victorian Paediatric Renal Service, Department of Nephrology, Royal Children's Hospital, Parkville, Victoria, Australia.
J M
JM
Forbes
T D
TD
Hewitson
G J
GJ
Becker
C L
CL
Jones
D058186:Acute Kidney Injury / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D002455:Cell Division / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D005260:Female; D020287:In Situ Nick-End Labeling; D007189:Indans / Q000494:pharmacology; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012079:Renal Circulation; D013997:Time Factors
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D007189:Indans; D011720:Pyrazoles; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C113973:SB 234551; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-