Chemokines, chemokine receptors and renal disease.

gesting that, at least in this model, MCP-1 promoted Chemokines are proinflammatory cytokines that funcnearly exclusively tubular epithelial cell damage [5]. tion in leukocyte chemoattraction and activation. There Contrasting with the ample information about chemoare two major families of chemokines, termed CXC and kines and renal injury, so far, little is known about the CC, according to the presence or absence of an amino expression and distribution of chemokine receptors on acid between a pair of cysteine residues near the NH2 different cells in normal and diseased kidneys. In this terminal [1, 2]. CXC chemokines [of which interleukin-8 issue of Kidney International, Segerer et al studied, by (IL-8) is the prototype] act on neutrophils and nonhemomeans of monoclonal antibodies, the distribution of poietic cells involved in wound healing, whereas CC cheCCR5 (that binds to RANTES, MIP-1 and MIP-1b, but mokines have a wider spectrum of action and they are not MCP-1) in 80 biopsies from patients with various active on monocytes, T and B lymphocytes, natural killer glomerulonephritis, acute and chronic interstitial nephri(NK) cells and dendritic cells, and they are, therefore, tis, and acute and chronic transplant rejection [6]. The of great relevance in renal disease [3]. Monocytes and most striking finding was that staining for CCR5 was tissue macrophages are rich sources of CC chemokines, only detected in areas of interstitial infiltrating cells with usually associated with de novo synthesis. Monocyte chethe same distribution as CD3-positive T cells. Absence or moattractant protein-1 (MCP-1) and MCP-2 are major near absence of staining for CCR5 in infiltrating CD-68 products of stimulated monocytes. Lymphocytes are positive macrophages, and in intrinsic renal cells, were sources of some chemokines, particularly RANTES, noted in nearly all the kidney diseases examined. The macrophage inflammatory protein-1 (MIP-1) and MIP-1b. lack of CCR5 expression by monocytes/macrophages in Endothelial cells, fibroblasts, epithelial cells and other the glomerulonephritis studied, mainly systemic lupus kidney cells also produce CC chemokines after approerythematosus (SLE), was unexplained. However, it could priate stimuli. Chemokines act through interaction with be speculated that other chemokines besides RANTES, seven transmembrane domain G-coupled receptors. So such as MCP-1, released by glomerular and tubular cells far, nine receptors have been identified for the CC cheduring renal injury, may be responsible for the recruitmokines (CCR1 to -9), and four for the CXC chemokines ment of macrophages. In fact, various CC and CXC (CXCR1 to -4). Chemokine receptors show a promiscuchemokines may be released during glomerular damage. ous pattern of ligand recognition and are differentially In addition, there are at least three monocyte CC chemoexpressed and regulated in leukocytes [1, 2]. kine receptors (CCR1, CCR2 and CCR5). One can asThe glomerular and interstitial infiltration of leukosume that CCR5-negative infiltrating cells, both at the cytes is a common phenomenon found in most renal disglomerular and interstitial level, should be positive for eases, independently of their immune or non-immune other chemokine receptors, most probably CCR2. In this origin. MCP-1 and RANTES are the most studied cheregard, mice deficient in CCR2 have severe reduction in mokines implicated in renal damage [3]. The importance leukocyte adhesion and monocyte extravasation after of MCP-1 and RANTES in anti-GBM nephritis was supintraperitoneal thioglycollate injection, indicating that ported by the reduction of glomerular damage after blockCCR2, after its stimulation by MCP-1, is a major regulaade of those chemokines by specific antibodies and receptor of macrophage trafficking in vivo. tor antagonists. However, although both chemokines seem The mechanisms that regulate expression of the cheto participate in glomerular inflammation, only MCP-1 mokine receptors are not well defined, but it is well was related to the crescentic and fibrogenic process, sugknown that cytokines can modify the density of receptors gesting that MCP-1 could also be involved in the turnin a particular cell. Thus, IL-2 increases the CCR1 and over of matrix proteins [4]. Surprisingly, MCP-1 deficient CCR2 expression, as well as the chemotactic responmice injected with nephrotoxic serum had a marked resiveness, in T lymphocytes. Lipopolysaccharide downduction in tubular, but not in glomerular, injury, sugregulates the expression of CCR2 in cultured monocytes, mostly due to the rapid degradation of CCR2 mRNA. Those cells are unresponsive to MCP-1 (which activates