Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function

Forbes, Josephine Maree, Hewitson, Timothy David, Becker, Gavin James and Jones, Colin Lindsay (2001) Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function. Kidney International, 59 4: 1333-1341. doi:10.1046/j.1523-1755.2001.0590041333.x

Author Forbes, Josephine Maree
Hewitson, Timothy David
Becker, Gavin James
Jones, Colin Lindsay
Title Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function
Journal name Kidney International   Check publisher's open access policy
ISSN 0085-2538
Publication date 2001-04
Sub-type Article (original research)
DOI 10.1046/j.1523-1755.2001.0590041333.x
Open Access Status Not yet assessed
Volume 59
Issue 4
Start page 1333
End page 1341
Total pages 9
Place of publication New York, NY, United States
Publisher Elsevier
Language eng
Formatted abstract
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 Mφ), myofibroblasts (MF, α-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 Mφ, 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.
Keyword End-stage renal disease
Endothelin receptor antagonists
SB 243551
Tubulointerstitial disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
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