This large cross-sectional study characterized relationships between serum MCP-1, albuminuria, eGFR and CP in the understudied AA population with T2D. After adjusting for covariates, higher serum MCP-1 levels associated positively with albuminuria and negatively with eGFR. In contrast, serum MCP-1 did not independently associate with atherosclerosis and subclinical CVD measured as CP, suggesting differential molecular relationships between inflammation, risk for kidney disease, and CVD in AAs with T2D.
The pathophysiologic connection between atherosclerosis, CAC, albuminuria and kidney dysfunction is poorly understood at the molecular level. Previous studies demonstrated that MCP-1 is involved in the pathophysiology of atherosclerosis and DN in T1D and T2D
[5, 7]. MCP-1 is synthesized and secreted by a myriad of cells (monocytes, macrophages, endothelial cells, renal mesangial and tubular cells); and both tissue and systemic cells can contribute to detectable serum MCP-1 levels. In the hyperglycemic milieu, MCP-1 is produced by resident renal endothelial cells, mesangial cells, podocytes, and tubular epithelial cells; as well as by circulating or infiltrating monocytes/macrophages
. Several reports attest to the positive correlation between tissue MCP-1 expression and urine levels with albuminuria, mesangial proliferation, and interstitial fibrosis in a wide range of kidney diseases in humans
[8, 31–36]. In small studies comprised of European-derived participants with T1D or T2D, ELISA-based measurements of serum MCP-1 did not correlate with albuminuria
[30, 34]. It has been proposed that while the histopathology in diabetic kidney disease has remarkable similarity between type 1 and type 2 diabetes, and between population groups, the pathogenetic background may differ between AAs and EAs, and T2D or T1D
. Other longitudinal studies comprised of EAs with T1D, found that urine MCP-1 levels were significantly higher in patients with early nephropathy (GFR<90 ml/min and microalbuminuria) relative to those without nephropathy, with no difference in serum MCP-1 levels.
[18, 19] Relative to EAs, it is possible that inflammatory pathways are upregulated in AAs. Previous studies have shown that AAs have higher serum CRP and interleukin-6 (IL-6) concentrations and display heightened oxidative stress and inflammation based on in vitro human umbilical vein endothelial cells (HUVECs) studies
[38, 39]. It is biologically plausible that MCP-1 may play differential roles in the pathophysiology of DN based on the type of diabetes and ethnic background.
We originally postulated that inflammation is a common mediator for both subclinical kidney disease and CVD in AAs with T2D and that systemic MCP-1 levels would correlate with markers of kidney disease and atherosclerosis. We found that a higher burden of vascular calcification was present in those with albuminuria, but CP did not associate with serum MCP-1 levels. Other studies demonstrated that serum MCP-1 levels correlate with CVD outcomes following acute coronary events, independent of traditional CVD risk factors
. Nevertheless, these studies did not examine the effect of serum MCP-1 on CV events based on kidney function or independent of the association with urine albumin excretion and eGFR. As in the present report, a large population-based sample from the Dallas Heart Study did not observe an association between serum MCP-1 and CAC after adjusting for age and other covariates
This is the first report of which we are aware detecting associations between serum MCP-1 with albuminuria and eGFR in AA patients with T2D and early nephropathy. Study participants were AAs without advanced kidney disease and no differences in serum MCP-1 levels were seen across genders. The nature of the factors determining elevated concentrations of serum MCP-1 in patients with T2D and early DN remains unknown. It is possible that high MCP-1 expression in the interstitial kidney macrophages leads to elevated systemic levels of MCP-1 proportional to the inflammatory and nephropathy stage. Another possibility, not mutually exclusive, is that serum MCP-1 levels are elevated in patients with early nephropathy due to dysregulated activation of systemic leukocytes. Indeed, several studies confirm an aberrant production of inflammatory cytokines and chemokines by circulating lymphocytes and monocytes in T2D patients with nephropathy
. Decreased filtration of extra-renally synthesized MCP-1 is less likely, since a minority of participants had an eGFR below 60 ml/min/1.73m2.
In addition to roles of MCP-1 in atherosclerosis and kidney disease, several studies implicated MCP-1 in the pathophysiology of obesity and insulin resistance
[43, 44]. In our sample of AAs with T2D, significant correlations were observed between MCP-1 and BMI, but not with diabetes duration or HbA1c. The association between adipose tissue and MCP-1 raised the question whether the link between serum MCP-1 and renal function parameters could have been driven by the high prevalence of obesity in this cohort. Adjustment for BMI and cholesterol failed to modify the association and BMI-stratified effect sizes were not statistically different between obese and non-obese strata. As such, relationships between serum MCP-1 and kidney function were not impacted by obesity.
Significant relationships between MCP-1 with eGFR and albuminuria, coupled with lack of association with CP, imply that MCP-1 does not mediate joint pathways implicated in co-existing kidney and CVD. However, the lack of a cross-sectional association between MCP-1 and burden of CP in AAs does not exclude a role for this molecule in the inflammatory component of atherosclerosis. Previous studies have shown that serum MCP-1 levels are higher in patients with active angina (compared to those with stable coronary disease), and higher levels predicted future coronary events and mortality following an acute coronary event
[45, 46]. In addition, serum MCP-1 levels have been associated with immunohistochemical indices of inflammation and matrix remodeling in the coronary atherosclerotic plaques of non-human primates
. The role of MCP-1 in CP should also be explored in EAs, a population with higher burden of vascular calcification than AAs
This study has important strengths and some limitations. AAs are known to display different patterns of nephropathy and CVD morbidity relative to EAs. The large and well phenotyped AA sample enabled simultaneous evaluation of a molecular biomarker potentially impacting albuminuria, eGFR, and subclinical atherosclerosis. Preserved kidney function in AA-DHS participants lessens concern that altered serum MCP-1 levels were due to kidney failure, whether mediated by poor renal excretion or inflammation-driven overproduction. Limitations include the cross-sectional nature of study measurements, rendering inability to secure a causal relationship between MCP-1 and early DN. Longitudinal studies characterizing relationships between MCP-1 and albuminuria and eGFR are warranted and could provide support for pharmacological MCP-1 inhibition during the incipient stages of DN
. Recent studies in mouse models suggest such treatment has promise
In conclusion, MCP-1 serum concentrations manifest positive association with albuminuria and negative association with eGFR in AAs with T2D; without association with subclinical atherosclerosis. Relationships between MCP-1, albuminuria, eGFR, and vascular CP need to be evaluated in EAs and non-diabetic AAs. MCP-1 inhibition could provide a novel therapeutic strategy to prevent diabetic kidney disease in AAs with T2D.