Time-dependent up-regulation of endothelin-A receptors and down-regulation of endothelin-B receptors and nitric oxide synthase binding sites in the renal medulla of a rabbit model of partial bladder outlet obstruction: potential clinical relevance.
OBJECTIVE
To assess the density of endothelin (ET) receptors (ET-1 is a potent vasoconstrictor peptide acting on two known receptors, ETA and ETB ) and nitric oxide synthase (NOS) binding sites in the kidney of a rabbit model of bladder outlet obstruction (BOO).


METHODS
Partial BOO was created in adult New Zealand White rabbits; after 1, 3, 4 and 6 weeks of BOO, kidney sections were incubated with radioligands for ET-1, ETA, ETB receptors and with [3H]-NOARG (a ligand for NOS). Autoradiographs were generated and analysed densitometrically. Sections were also assessed by NADPH histochemistry. Plasma creatinine, urea and electrolyte levels were regularly monitored. The control and 6-week BOO kidneys were also evaluated ultrastructurally by electron microscopy.


RESULTS
There was no significant change in plasma creatinine, urea and electrolyte levels. ETA and ETB receptor density was significantly greater in the medulla than in the cortex (P<0.001) in all animals. There was an up-regulation of ETA receptors (P=0.03) and down-regulation of ETB receptors (P=0.03) and NOS binding sites (P<0.001), as well as decreased NADPH staining in the medulla of 6-week partial BOO kidneys. Electron microscopy detected glomerular disruption of the obstructed kidneys.


CONCLUSIONS
The time-dependent changes in ETA and ETB receptors, NOS binding sites and NADPH staining in the renal medulla, as well as ultrastructural changes, occur despite normal renal function. These changes appear to be an early event and may play a role in the development of renal failure. Hence, the use of ETA receptor antagonists at this early stage may prevent the development of renal failure/impairment in BOO.
Khan
M A
MA
Department of Urology, Royal Free, University College Medical School, London, UK.
Dashwood
M R
MR
Thompson
C S
CS
Mumtaz
F H
FH
Mikhailidis
D P
DP
Morgan
R J
RJ
D058186:Acute Kidney Injury / Q000209:etiology; D000818:Animals; D001665:Binding Sites; D015536:Down-Regulation; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D001748:Urinary Bladder Neck Obstruction / Q000378:metabolism*
D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D019001:Nitric Oxide Synthase