Chemokine receptor 2b inhibition provides renal protection in angiotensin II - salt hypertension.
The present study was designed to determine whether chemokine receptor 2b (CCR2b) contributes to the development of renal injury in salt-sensitive angiotensin II (ANG) hypertension. Rats were infused with ANG and fed a high-salt diet (HS) for 14 days. Rats were divided into 4 groups: HS; HS administered the CCR2b antagonist, RS102895; Ang/HS hypertensive; and Ang/HS hypertensive administered RS102895. CCR2b inhibition slowed the progression of blood pressure elevation during the first week of ANG/HS hypertension; however, it did not alter blood pressure in the HS group. At 2 weeks, arterial pressure was not significantly different between ANG/HS and ANG/HS hypertensive rats administered RS102895. Renal cortical nuclear factor kappaB activity increased in ANG/HS hypertension compared with the HS group (0.11+/-0.006 versus 0.08+/-0.003 ng of activated nuclear factor kappaB per microgram of protein), and RS102895 treatment lowered nuclear factor kappaB activity in ANG/HS hypertension (0.08+/-0.005 ng of activated nuclear factor kappaB per microgram of protein). Renal tumor necrosis factor-alpha and intercellular adhesion molecule-1 expression increased, and Cyp2c23 expression decreased in ANG/HS hypertension compared with the HS group, and CCR2b inhibition reduced tumor necrosis factor-alpha and intercellular adhesion molecule-1 and increased Cyp2c23 expression. Histological immunostaining revealed increased renal monocyte and macrophage infiltration in ANG/HS hypertensive rats with decreased infiltration in rats receiving RS102895 treatment. Albuminuria and cortical collagen staining also increased in ANG/HS hypertensive rats, and RS102895 treatment lowered these effects. Afferent arteriolar autoregulatory responses to increasing renal perfusion pressure were blunted in ANG/HS hypertension, and RS102895 treatment improved this response. These data suggest that CCR2b inhibition protects the kidney in hypertension by reducing inflammation and delaying the progression of hypertension.
Elmarakby
Ahmed A
AA
Vascular Biology Center, Medical College of Georgia, Augusta 30912-2500, USA.
Quigley
Jeffrey E
JE
Olearczyk
Jeffrey J
JJ
Sridhar
Aarthi
A
Cook
Anthony K
AK
Inscho
Edward W
EW
Pollock
David M
DM
Imig
John D
JD
D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology; D003094:Collagen / Q000032:analysis; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007668:Kidney / Q000187:drug effects*; D008264:Macrophages / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C000717351:Cyp2c23 protein, rat; D016328:NF-kappa B; D054390:Receptors, CCR2; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2