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2013 ; 61
(6
): 1218-26
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Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response
via interleukin-10: role in renoprotection in obese rats
#MMPMID23547236
Dhande I
; Ali Q
; Hussain T
Hypertension
2013[Jun]; 61
(6
): 1218-26
PMID23547236
show ga
The angiotensin type 2 receptor (AT2R) has been shown to lower inflammation in
the kidney. However, the role of the anti-inflammatory cytokine interleukin
(IL)-10 in AT2R-mediated attenuation of inflammation has not been elucidated. We
hypothesized that AT2R activation is renoprotective by directly increasing the
levels of anti-inflammatory cytokine IL-10 in the kidney via nitric oxide (NO)
signaling. For in vitro studies, the human proximal tubule epithelial cell-line
(human kidney-2 [HK-2]) was activated with lipopolysaccharide (10 ?g/mL) and AT2R
agonist C21 (1 ?mol/L) for 24 hours, and media cytokine levels were assessed.
Lipopolysaccharide modestly downregulated AT2R expression. Treatment with C21
lowered lipopolysaccharide-induced levels of both tumor necrosis factor-? and
IL-6, but increased IL-10 levels. Treatment with neutralizing IL-10 antibody (1
?g/mL) or NO synthase inhibitor L-NAME (1 mmol/L) abolished this effect. For in
vivo studies, prehypertensive obese Zucker rats and age-matched lean Zucker rats
were treated for 2 weeks with C21 (300 ?g/kg per day, IP) and AT2R antagonist
(PD123319; 50 ?g/kg per minute, SC infusion). Compared with lean Zucker rats,
obese Zucker rats had higher levels of renal AT2R expression, tumor necrosis
factor-?, and IL-6. C21 treatment decreased levels of tumor necrosis factor-? by
75% and IL-6 by 60%. Conversely, PD treatment lowered the renal IL-10 levels in
obese Zucker rats by ?60%. Renal morphometry revealed increased mesangial matrix
expansion and glomerular macrophage infiltration, which was improved by C21
treatment in obese Zucker rats. Our findings suggest that proximal tubule AT2R
activation is anti-inflammatory by increasing IL-10 production, which is largely
NO dependent and thus offers renoprotection by preventing early
inflammation-induced renal injury in obesity.
|Animals
[MESH]
|Blotting, Western
[MESH]
|Disease Models, Animal
[MESH]
|Enzyme-Linked Immunosorbent Assay
[MESH]
|Humans
[MESH]
|Inflammation/metabolism/pathology
[MESH]
|Interleukin-10/*pharmacology
[MESH]
|Kidney Diseases/*metabolism/pathology/prevention & control
[MESH]