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Acute toll‐like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour
Author(s) -
Van Beusecum J. P.,
Zhang S.,
Cook A. K.,
Inscho E. W.
Publication year - 2017
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.12899
Subject(s) - arteriole , afferent arterioles , losartan , medicine , endocrinology , candesartan , angiotensin ii receptor type 1 , receptor , tlr4 , angiotensin ii , chemistry , lipopolysaccharide , vasoconstriction , microcirculation
Aim Little is known about how toll‐like receptor 4 ( TLR 4) influences the renal microvasculature. We hypothesized that acute TLR 4 stimulation with lipopolysaccharide ( LPS ) impairs afferent arteriole autoregulatory behaviour, partially through reactive oxygen species ( ROS ). Methods We assessed afferent arteriole autoregulatory behaviour after LPS treatment (1 mg kg −1 ; i.p.) using the in vitro blood‐perfused juxtamedullary nephron preparation. Autoregulatory behaviour was assessed by measuring diameter responses to stepwise changes in renal perfusion pressure. TLR 4 expression was assessed by immunofluorescence, immunohistochemistry and Western blot analysis in the renal cortex and vasculature. Results Baseline arteriole diameter at 100 mmHg averaged 15.2 ± 1.2 μ m and 12.2 ± 1.0 μ m for control and LPS groups ( P < 0.05) respectively. When perfusion pressure was increased in 15 mmHg increments from 65 to 170 mmHg, arteriole diameter in control kidneys decreased significantly to 69 ± 6% of baseline diameter. In the LPS ‐treated group, arteriole diameter remained essentially unchanged (103 ± 9% of baseline), indicating impaired autoregulatory behaviour. Pre‐treatment with anti‐ TLR 4 antibody or the TLR 4 antagonist, LPS ‐ RS , preserved autoregulatory behaviour during LPS treatment. P2 receptor reactivity was normal in control and LPS ‐treated rats. Pre‐treatment with Losartan (angiotensin type 1 receptor blocker; ( AT 1 ) 2 mg kg −1 ; i.p.) increased baseline afferent arteriole diameter but did not preserve autoregulatory behaviour in LPS ‐treated rats. Acute exposure to Tempol (10 −3 mol L −1 ), a superoxide dismutase mimetic, restored pressure‐mediated vasoconstriction in kidneys from LPS ‐treated rats. Conclusion These data demonstrate that TLR 4 activation impairs afferent arteriole autoregulatory behaviour, partially through ROS , but independently of P2 and AT 1 receptor activation.