Fractalkine and its receptor, CX3CR1, promote hypertensive interstitial fibrosis in the kidney

Abstract

Hypertension promotes and escalates kidney injury, including kidney fibrosis. Fractalkine/CX3CL1 is a unique chemokine that works as a leukocyte chemoattractant and an adhesion molecule. Recently, fractalkine/CX3CL1 has been reported to promote tissue fibrosis via its cognate receptor, CX3CR1. However, the involvement of the fractalkine-CX3CR1 axis in the pathogenesis of hypertensive kidney fibrosis remains unclear. The impacts of the fractalkine-CX3CR1 axis on hypertensive kidney fibrosis were investigated in a deoxycorticosterone acetate (DOCA)-salt hypertensive model in CX3CR1-deficient mice, which were sacrificed on day 28. The blood pressure levels were similarly elevated in both CX3CR1À/À C57BL/6 and wild-type C57BL/6 mice. Fractalkine and CX3CR1 were upregulated in kidneys that were damaged by hypertension. Deficiency in CX3CR1 inhibited kidney fibrosis, as evidenced by a decrease in the presence of interstitial fibrotic area detected by type I collagen in MalloryAzan staining, concomitant with the downregulation of transforming growth factor (TGF)-b 1 and type I procollagen mRNA expression in damaged kidneys. The CX3CR1 blockade also decreased the number of infiltrating F4/80-positive macrophages in damaged kidneys. These results suggest that the fractalkine-CX3CR1 axis contributes to kidney fibrosis in a hypertensive mouse model, possibly by the upregulation of macrophage infiltration and the expression of TGF-b 1 and type I collagen.

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

“…In this paper, we report a previously undescribed antifibrotic effect of CX 3 CR1: it reduced the inflammation-induced proliferation of TGF-b-producing renal macrophages, which are critically important in experimental kidney fibrosis (15)(16)(17)(18). This finding was unexpected, given the proinflammatory and profibrotic properties of CX 3 CR1 not only in diseases of the kidney (3,49,54,(57)(58)(59)65), but also of the lung (75), liver (50), intestine (28), skin (55), arteriosclerotic vessels (76), and the CNS (33). CX 3 CR1 has been shown to contribute to the inflammatory recruitment of monocytes from the circulation into all these organs (44).…”

“…DC numbers are severely reduced in CX 3 CR1-deficient mice (3), which would be consistent with altered differentiation. DCs do not play a major role in UUO, whereas macrophages are critical (18,49,54). This is not unexpected given that DCs primarily regulate adaptive immune responses, explaining why they affected fibrosis in models that involve adaptive immune cells, such as ischemia/reperfusion injury, crescentic glomerulonephritis and hypertensive nephropathy (3,49,54,57).…”

“…The chemokine receptor CX 3 CR1 has been shown to promote renal inflammation in several models (3,49,54,(57)(58)(59)65). Given that chronic kidney inflammation often leads to fibrosis, we hy- pothesized that CX 3 CR1 deficiency should attenuate renal fibrosis.…”

“…CX 3 CR1 deficiency reduced entry of their progenitors into the kidney and attenuated symptoms and fibrosis in ischemia/reperfusion injury (44,49), hypertensive kidney damage (54), and crescentic glomerulonephritis (3,57). In contrast, the loss of renal phagocytes aggravated renal candidiasis (58) but not pyelonephritis (3).…”

“…Also, CX 3 CR1 has been implicated in monocyte recruitment into inflamed tissues, like arteriosclerotic vessels (45), the listeria-infected spleen (46), the eye (47), in colitis models (28), or the skin (48). Furthermore, CX 3 CR1 may exert profibrotic functions (49)(50)(51)(52)(53)(54)(55).…”