Chemokine Receptor 2b Inhibition Provides Renal Protection in Angiotensin II–Salt Hypertension

Abstract

Abstract-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 B activity increased in ANG/HS hypertension compared with the HS group (0.11Ϯ0.006 versus 0.08Ϯ0.003 ng of activated nuclear factor B per microgram of protein), and RS102895 treatment lowered nuclear factor B activity in ANG/HS hypertension (0.08Ϯ0.005 ng of activated nuclear factor B per microgram of protein). Renal tumor necrosis factor-␣ 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-␣ 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. Key Words: kidney Ⅲ inflammation Ⅲ hypertension Ⅲ angiotensin Ⅲ MCP-1 Ⅲ CCR2b Ⅲ chemokines S tudies suggest that inflammation is involved in the progression of hypertension-induced kidney diseases. 1 Cytokines have been identified as components of this inflammation. Chemokines are a class of cytokines that are involved in the proinflammatory response in both normal and pathological conditions. 1 The main function of chemokines is to promote leukocyte migration to sites of injury, and this is achieved through ligand/receptor binding with receptors expressed on leukocytes. 2 Through chemokine signaling, monocytes infiltrate tissue, differentiate into macrophages, and release additional chemokines perpetuating the inflammatory cycle.Monocyte chemoattractant protein-1 (MCP-1) plays a pivotal role in the development of the inflammatory response. 1 MCP-1 expression increases at injury sites to direct macrophage recruitment. 2 Mechanistically, MCP-1 binds to the inducible C-C chemokine receptor 2 (CCR2) to promote chemotaxis. 3 There are 2 known subtypes of CCR2, CCR2...

High-NaCl intake impairs dynamic autoregulation of renal blood flow in ANG II-infused rats

“…However, it is important to recognize that impaired dynamic RBFA does not indicate a certain level of RBF at a certain level of AP, but more likely predicts whether the response of RBF following a dynamic change in arterial pressure will be normal. In line with our results, Elmarakby et al (13) showed that autoregulatory responses of afferent arterioles to step-wise increases in perfusion pressure were blunted in ANG II-infused rats on high dietary NaCl (13). However, in that study no comparison was made to ANG II-infused animals on a normal NaCl intake.…”

“…However, the pathophysiological mechanisms by which hypertension causes renal injury are multiple and incompletely understood (13,27,28,34). The results of the present study suggest that a very high-NaCl intake in ANG II-dependent forms of hypertension, in addition to elevating AP further, could increase the susceptibility to hypertensive glomerular injury by impairing RBFA.…”

“…tubuloglomerular feedback; superoxide; myogenic response HYPERTENSION IS A COMMON CAUSE of kidney injury and end-stage renal disease and accelerates loss of kidney function in patients with chronic kidney disease, regardless of the underlying etiology (19). However, the risk of renal injury is variable, and the pathophysiological mechanisms by which hypertension causes renal parenchymal injury are complex and incompletely understood (5,13,27,28,34). The renal blood flow (RBF) autoregulatory response, mediated mainly by the myogenic response (MR) and the tubuloglomerular feedback mechanism (TGF), stabilizes RBF and glomerular filtration rate (GFR), despite wide variations in arterial blood pressure (AP) (9, 23).…”

“…However, the risk of renal injury is variable, and the pathophysiological mechanisms by which hypertension causes renal parenchymal injury are complex and incompletely understood (5,13,27,28,34). The renal blood flow (RBF) autoregulatory response, mediated mainly by the myogenic response (MR) and the tubuloglomerular feedback mechanism (TGF), stabilizes RBF and glomerular filtration rate (GFR), despite wide variations in arterial blood pressure (AP) (9,23).…”

Role of the monocyte chemoattractant protein-1/C-C chemokine receptor 2 signaling pathway in transient receptor potential vanilloid type 1 ablation-induced renal injury in salt-sensitive hypertension

“…3 There is accumulating evidence showing that inhibition of CCR2 attenuates renal injury in renal diseases. [4][5][6] These studies clearly indicate a role for CCR2 in the development of renal disease. The transient receptor potential vanilloid type 1 (TRPV1, also known as VR1) channel is originally found in primary sensory neurons that innervate various tissues including the heart, blood vessel, and kidney.…”