Role of Chemokine (C–X–C Motif) Ligand 10 (CXCL10) in Renal Diseases

Table 1

The spectrum of kidney diseases in which CXCL10 involved.

(a) Mesangial proliferative glomerulonephritis (MesPGN)

Function	Authors and year [Ref]	Studied subjects	Endpoints
CXCL10 promotes mesangial cell proliferation	Romagnani P et al. 1999 [30]	Patients/renal biopsies; HMCs	High expression of CXCR3 by mesangial cells of patients with IgA nephropathy, membranoproliferative glomerulonephritis, or rapidly progressive glomerulonephritis.; CXCL10 mediate both intracellular Ca^2+ influx and HMC proliferation.
	Romagnani P et al. 2002 [33]	Patients/renal biopsies HMCs	Double-label immunohistochemical analysis for PCNA and α-SMA demonstrated that CXCL10 synthesis by resident glomerular cells was an extremely selective property of kidneys exhibiting PGN.; The production of IP-10 and Mig by HMC can be downregulated by NO donors through cGMP-independent inhibition of NF-kappaB activation.
	Gao J et al. 2017 [55].	Cxcl10-deficient mice/ Habu nephritis model; MMCs	Cxcl10^-/- mice exhibited mitigated mesangial proliferation via the ERK signaling pathway.
	Wörnle M et al. 2004 [54]	HMCs	CXCL10 induced HMC proliferation in a dose-dependent manner.
CXCL10 promotes mesangial cell apoptosis	Wu L et al. 2015 [27]	Mxi1-deficient mice/Habu nephritis model; MMCs	CXCL10 expression induced by Mxi1 inactivation leads to mesangial cell apoptosis in murine Habu nephritis.; CXCL10 expression was induced by TLR4–IRF3 signaling in Mxi1-inactivated mouse mesangial cells (MMCs).
CXCL10 maintains podocyte function	Han GD et al. 2003 [29]	Wistar rats/Thy1.1 GN mouse podocytes	The anti-IP-10 treatment given to the rats with Thy1.1 nephritis decreased the expression of nephrin and podocin, accompanied by exacerbated proteinuria, mesangiolysis, and matrix expansion.

(b) Acute kidney injury (AKI)

Function	Authors and year [Ref]	Studied subjects	Endpoints
CXCL10 as a potential injury biomarker of AKI	Ho J. et al. 2009 [67]	Patients/serum and urine	CXCL10 was upregulated postoperatively in patients with AKI, which corresponds temporally to the later phase(s) of tubular injury unique to patients with AKI.
	Vaidya V et al. 2008 [68]	Patients/urine	Urinary concentration of CXCL10 was significantly elevated in patients with clinically established AKI.
	E. Bautista et al. 2013 [69].	Patients/serum	Patients with influenza A/H1N1 infection and ARDS/AKI have an overproduction of IP-10 possibly contributing to kidney injury and are associated to a higher risk of death.
CXCR3 promotes recruitment of T cells	Fiorina P et al. 2006 [70]	CXCR3-deficient mice/renal I/R injury	CXCR3^-/- mice exhibited attenuated renal dysfunction and a lower percentage of CD4^+IFN-gamma^+ cells.
	Tsutahara K et al. 2012 [71].	Sprague-Dawley rats/renal I/R injury	The blocking of CXCR3 and CCR5 suppresses the infiltration of T lymphocytes.
CXCL10 inhibits renal tubular cell proliferation	Furuichi K et al. 2008 [39]	BALB/c mice/renal I/R injury; Murine tubular epithelial cells	The numbers of Ki67-positive proliferating tubular cells were significantly increased in anti-CXCL10 Ab-treated mice after reperfusion.

(c) Lupus nephritis (LN)

Function	Authors and year [Ref]	Studied subjects	Endpoints
CXCL10 as an effective predictor of LN	Avihingsanon et al. 2006 [80].	Patients/urine	Urinary CXCL10 and CXCR3 levels could distinguish class IV LN from others with an accuracy greater than the current available clinical markers.
	Morimoto et al. 2009 [81].	Patients/serum	Increased serum CXCL10 level was found in patients with proliferative LN (World Health Organization (WHO) classes III and IV).
	Enghard P et al. 2009 [82].	Patients/renal biopsies, peripheral blood and urine	A selective enrichment of CXCR3^+CD4^+ T cells was found in the urine, and CXCR3 expression on urinary T cells correlated with disease activity as determined by the SLEDAI.
	Marie MA et al. 2014 [83].	Patients/urine	CXCL10 was considered a highly valid predictor of SLE nephritis with high sensitivity (100%) and specificity (98%).
Conflicting evidences on the reliability of CXCL10 as a diagnostic biomarker	Abujam B et al. 2013 [84].	Patients/serum and urine	Urinary CXCL10 was indicative of renal activity but was not better than conventional markers.
	El-Gohary A et al. 2016 [85].	Patients/serum and urine	No difference between LN and SLE patients without renal involvement nor between active renal SLE and active non-renal SLE patients.
	Watson L et al. 2012 [86].	Patients/urine	Urinary concentrations of CXCL10 could not distinguish active from non-active renal disease in patients with juvenile-onset systemic lupus erythematosus (JSLE).
	Lu J et al. 2011 [87].	Patients/renal biopsies	CXCR3 pathway is important in determining clinical severity rather than the histological pattern of LN.; No difference in glomerular and tubulointerstitial CXCL10 expression between LN patients and controls.
CXCR3 mediates renal Th1 and Th17 immune response	Steinmetz OM et al. 2009 [89].	CXCR3^-/- MRL/lpr mice	CXCR3^-/- MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment.
CXCR3 promotes the production of IgG1 autoantibodies	Moser K et al. 2012 [90].	CXCR3^-/- NZB/NZW mice	CXCR3 has an effect on (auto)antibody production but is not essential for lupus pathogenesis in NZB/NZW mice.
CXCR3 increases MSCs infiltration	Lee JH et al. 2018 [91].	MRL.Fas^lpr mice	CXCR3-deficient mesenchymal stem cells fail to infiltrate into the nephritic kidney and do not ameliorate lupus symptoms in MRL.Fas^lpr mice

(d) Renal transplantation rejection

Function	Authors and year [Ref]	Studied subjects	Endpoints
Enhanced CXCL10 production in the graft of AR	Segerer S et al. 2001 [92].	Patients/renal biopsies	Increased CXCL10 mRNA expression in transplant nephrectomy specimens from patients with acute rejection (AR) by RNase protection assay.
	Matl I et al. 2010 [93].	Patients/renal biopsies	Higher CXCL10 mRNA expression in subclinical rejection, including borderline changes.; Higher intrarenal CXCL10 expression implied an increased risk of renal graft failure within one year after transplantation.
	Lo DJ et al. 2011 [94].	Patients/renal biopsies	CXCL10 and CXCR3 expression levels were significantly elevated in allografts with subclinical or clinical AR.
Elevated serum CXCL10 expression in AR	Rotondi M et al. 2004 [96]	Patients/serum	High pretransplant CXCL10 serum levels represent an important predictor of the risk of kidney graft rejection and transplant failure.
	Huang H et al. 2014 [97].	Patients/serum	High serum CXCL10 concentrations have been detected using luminex analysis during AR episodes.
	Mao Y et al. 2011 [98].	Patients/serum	CXCL10 were highly up-regulated in peripheral blood mononuclear cells in acute rejection and poor response to anti-rejection therapy.
Urinary CXCL10 as a potential noninvasive biomarkers for AR	Schaub et al. 2009 [102]	Patients/urine	CXCL9/CXCL10 potential noninvasive biomarkers for subclinical tubulitis.
	Ho et al. 2011 [103]	Patients/urine	CXCL10 : Cr sensitivity of 73.3% and specificity of 72.7%.
	M. Matz et al. 2006 [101]	Patients/urine	Incidence of AR: Urinary IP-10 protein observed 2/3 d prior to biopsy with 71% sensitivity and 95% specificity.; Long term graft function: Urinary IP-10 predictive of GFR at 6 month posttransplant.
	P. Hirt-Minkowski et al. 2012 [104]	Patients/urine	Urinary CXCL10 levels correlate with the extent of (sub) clinical tubulointerstitial inflammation.
	D. E. Hricik et al. 2013 [106]	Patients/urine	Urinary CXCL9 is a risk-stratifying biomarker for kidney transplant injury.