ABSTRACT: Inflammation plays a major role in the pathogenesis of diabetic nephropathy (DN) and may be a potential reason for the disparity in DN and end stage renal disease (ESRD) in African Americans (AAs). We have recently observed a strong association between C-reactive protein (CRP; a potent marker of inflammation) and urinary albumin excretion (UAE; an early marker of kidney disease) in patients with type 2 diabetes. The levels of CRP and UAE were significantly higher in AAs compared to Whites, suggesting that inflammatory processes of DN may be influenced by ethnicity. CRP promotes the differentiation of human monocytes towards a pro-inflammatory (M1) macrophage phenotype. Macrophages have been shown to play a critical role in the pathogenesis of DN in patients and experimental models and their accumulation and activation correlate with the development of DN. Therefore, based upon our previous work and published literature, we hypothesize that: i) circulating inflammatory markers, such as CRP, are associated with the progression of DN in AAs, and ii) M1 polarization of macrophage is more abundant in AAs, compared to whites possibly due to M-CSF and GM-CSF-dependent signaling that differentially modulates the cJun-Alox5 pathway. To test our hypotheses, we will perform descriptive statistics to show that increased levels of CRP in AA participants are directly correlated with the severity and progression of DN in longitudinal follow-up data at the Jackson Heart Study. We will also culture commercially available peripheral blood monocytes from AA and White to test cJun-Alox5 pathway. Our results should have a substantial impact to clarify the potential role of inflammatory markers, such as CRP in the severity and progression of DN in AAs. It will also help us to understand the molecular basis of disparities in DN in AAs and the underlying mechanisms of functional polarization of macrophage, thus providing new insights into a basis for targeting macrophage-mediated inflammation in DN.
SIGNIFICANCE: Although the incident rates of diabetes (DM)-related ESRD has recently stabilized, the rates in high-risk groups, such as AAs continue to increase. Approximately 30% of patients with DM develop DN, which accounts for ~44% of ESRD in the United States. In 2011, the managing cost for DN itself in the US was ~$34.4 billion per annum. Racial minority populations are disproportionately affected by DM and its complications, particularly DN and ESRD. The 2013 report from the US Renal Data System showed that the incidence of diabetic ESRD in AA was 940 per million populations, while in whites it was 280 per million. In addition, ethnic differences alter the rate of progression of DN, and AAs have a more rapid course than whites. In a cross sectional study, a stronger association between CRP and albumin-to-creatinine ratio (ACR) in non-white men and AA women suggest that the inflammatory process of DN may be influenced by ethnicity and sex. A complex interplay between mononuclear phagocytic lineage cells, growth factors, cytokines and chemokines may contribute to these disparities. Inflammation in the kidney involves infiltration of mф and the production of growth factors, pro-inflammatory cytokines, such as IL-1, IL-6, IL-18 and TNF-α, that may contribute directly or indirectly to the progression of DN. Increased expression of these cytokines has been reported in patients with DN. It is also known that mф infiltrate the glomeruli and/or interstitium in the kidney tissue in patients with DN, and the intensity of the interstitial infiltrate is proportional to the rate of subsequent decline in renal function. Other cells also may play a role in the inflammatory process in the kidney. For example, proximal tubular epithelial cells have been shown to produce the chemokine MCP-1. However, mф are the predominant infiltrating immune cells mediating the inflammatory process. Different therapeutic strategies to prevent the development or reduce renal injury in DM are associated with anti-inflammatory actions but currently; treatment to prevent the progression of DN is still suboptimal.
The significance of this proposed study is that a better understanding of the inflammatory process of DN in AA participants in the JHS is central to devising novel therapeutic and preventive treatment strategies to potentially eliminate the disparities. This will also allow us to further investigate racial/ethnic differences in the severity and progression of DN in other cohorts such as the Atherosclerosis Risk In Communities (ARIC). Therapeutic mф targeting is in its infancy. The identification of mechanisms and molecules associated with mф plasticity and polarized activation provides a basis for mф -centered diagnostic and therapeutic strategies. Thus, the specific implication of this grant will be to provide a foundation to develop novel therapies that target ALOX5 to prevent mф -mediated inflammation in DN. Our results may provide the basis for translational studies to implement anti-inflammatory therapy in order to diminish the disparity in DN in AAs.