Fiery Connections: Macrophage-Mediated Inflammation, the Journey from Obesity to Type 2 Diabetes Mellitus and Diabetic Kidney Disease.

The high prevalence of diabetes mellitus (DM) poses a significant public health challenge, with diabetic kidney disease (DKD) as one of its most serious consequences. It has become increasingly clear that type 2 DM (T2D) and the complications of DKD are not purely metabolic disorders. This review outlines emerging evidence related to the step-by-step contribution of macrophages to the development and progression of DKD in individuals who specifically develop T2D as a result of obesity.

Anti-Inflammatory Oxysterol, Oxy210, Inhibits Atherosclerosis in Hyperlipidemic Mice and Inflammatory Responses of Vascular Cells.

Background And Aims: We previously reported that Oxy210, an oxysterol-based drug candidate, exhibits antifibrotic and anti-inflammatory properties. We also showed that, in mice, it ameliorates hepatic hallmarks of non-alcoholic steatohepatitis (NASH), including inflammation and fibrosis, and reduces adipose tissue inflammation. Here, we aim to investigate the effects of Oxy210 on atherosclerosis, an inflammatory disease of the large arteries that is linked to NASH in epidemiologic studies, shares many of the same risk factors, and is the major cause of mortality in people with NASH.

Pathomechanisms of Diabetic Kidney Disease.

The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage.

Osteopontin as a Biomarker in Chronic Kidney Disease.

Osteopontin (OPN) is a ubiquitously expressed protein with a wide range of physiological functions, including roles in bone mineralization, immune regulation, and wound healing. OPN has been implicated in the pathogenesis of several forms of chronic kidney disease (CKD) where it promotes inflammation and fibrosis and regulates calcium and phosphate metabolism. OPN expression is increased in the kidneys, blood, and urine of patients with CKD, particularly in those with diabetic kidney disease and glomerulonephritis.

Vitamin D3 Repletion Improves Vascular Function, as Measured by Cardiorenal Biomarkers in a High-Risk African American Cohort.

Background: 25-hydroxy vitamin D (Vit D)-deficiency is common among patients with chronic kidney disease (CKD) and contributes to cardiovascular disease (CVD). African Americans (AAs) suffer disproportionately from CKD and CVD, and 80% of AAs are Vit D-deficient. The impact of Vit D repletion on cardio-renal biomarkers in AAs is unknown.

Roles of Macrophages in Atherogenesis.

Atherosclerosis is a chronic inflammatory disease that may ultimately lead to local proteolysis, plaque rupture, and thrombotic vascular disease, resulting in myocardial infarction, stroke, and sudden cardiac death. Circulating monocytes are recruited to the arterial wall in response to inflammatory insults and differentiate into macrophages which make a critical contribution to tissue damage, wound healing, and also regression of atherosclerotic lesions. Within plaques, macrophages take up aggregated lipoproteins which have entered the vessel wall to give rise to cholesterol-engorged foam cells.

Local M-CSF (Macrophage Colony-Stimulating Factor) Expression Regulates Macrophage Proliferation and Apoptosis in Atherosclerosis.

Objective: Previous studies have shown that deficiency of M-CSF (macrophage colony-stimulating factor; or CSF1 [colony stimulating factor 1]) dramatically reduces atherosclerosis in hyperlipidemic mice. We characterize the underlying mechanism and investigate the relevant sources of CSF1 in lesions. Approach and Results: We quantitatively assessed the effects of CSF1 deficiency on macrophage proliferation and apoptosis in atherosclerotic lesions.

How Clinically Relevant Is C-Reactive Protein for Blacks with Metabolic Syndrome to Predict Microalbuminuria?

The metabolic syndrome (MetS) is associated with elevated urinary albumin (UA) excretion and C-reactive protein (CRP). However, potential differences in CRP levels on the association between individual components of the MetS and microalbuminuria (MA; 30-300 μg/mL) and/or UA (0-300 μg/mL) by race/ethnicity is unknown. We analyzed National Health and Nutrition Examination Surveys (NHANES) data, (1999-2010) for adults (≥20 years of age) with the MetS ( = 5700).

hs-CRP Is Associated With Incident Diabetic Nephropathy: Findings From the Jackson Heart Study.

Objective: African Americans (AA) suffer disproportionately from diabetic nephropathy (DN). C-reactive protein (CRP) has been associated with prevalent DN, but its association with incident DN in AA is unknown. We examined hs-CRP and incident DN in AA.

Role of macrophage colony-stimulating factor in the development of neointimal thickening following arterial injury.

Evidence suggests that macrophage colony-stimulating factor (M-CSF) participates critically in atherosclerosis; little is known about the role of M-CSF in the development of neointimal hyperplasia following mechanical vascular injury. We examined the expression of M-CSF and its receptor, c-fms, in rodent and rabbit models of arterial injury. Injured rat carotid arteries expressed 3- to 10-fold higher levels of M-CSF and c-fms mRNA and protein following balloon injury as compared to uninjured arteries.

Multinucleated giant cells in atherosclerotic plaques of human carotid arteries: Identification of osteoclast-like cells and their specific proteins in artery wall.

Unlabelled: The mechanism(s) mediating atherosclerotic calcification may be similar to those governing bone remodeling, and osteoblast-like cells have been observed in plaque. We tested the hypothesis that osteoclast-like cells (OLCs) also exist in atherosclerotic arteries. In 205 tissue blocks obtained from 21 patients undergoing carotid endarterectomy, we performed histopathologic analysis, histochemical staining for tartrate-resistant acid phosphatase (TRAP), and immunohistochemical analysis for osteoclast and macrophage antigens, including CD68, colony stimulating factor-1 receptor (CSF-1R), cathepsin K (cat-K), receptor activator of nuclear factor-κB (RANK), and osteoprotegerin (OPG).

Effects of G-CSF on serum cholesterol and development of atherosclerotic plaque in apolipoprotein E-deficient mice.

Unlabelled: Macrophage colony stimulating factor (M-CSF) is known to have profound effects upon vascular pathologies, but potential roles of other colony stimulating factors (CSF) are not well understood. We treated apo E deficient (apo E-/-) mice with granulocyte colony stimulating factor (G-CSF) or vehicle daily for 9 weeks, during which time they were fed a Western-style diet. G-CSF treatment resulted in increased proportions of circulating monocytes (6.

Association of race/ethnicity, inflammation, and albuminuria in patients with diabetes and early chronic kidney disease.

OBJECTIVE African Americans (AAs) and Hispanics have higher diabetes and end-stage renal disease but similar or lower early chronic kidney disease (CKD) compared with whites. Inflammation plays a critical role in the pathogenesis of diabetes-related CKD. We postulated that in contrast to the general population, AAs and Hispanics have a higher prevalence of early diabetic CKD and systemic inflammatory markers compared with whites.

Nuclear localization of catalytically active MMP-2 in endothelial cells and neurons.

From microscopic organelles and sub-cellular domains to the level of whole tissues, organs, and body parts, living organisms must continuously maintain and renovate structural components. Matrix metalloproteinases (MMPs) comprise a family of over two dozen Zn-dependent endopeptidases thought to be primary effectors of extracellular tissue renewal and remodeling processes. Endogenous inhibitors, particularly the tissue inhibitors of MMPs (TIMPs), counteract MMP-2 proteolytic activity, but also participate in conversion of several pro-MMPs to proteolytically active forms.

Decreased prevalence of diabetes in marijuana users: cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III.

Objective: To determine the association between diabetes mellitus (DM) and marijuana use.

Design: Cross-sectional study.

Setting: Data from the National Health and Nutrition Examination Survey (NHANES III, 1988-1994) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention.

17β-estradiol inhibits oxidized low-density lipoprotein-induced increase in matrix metalloproteinase-9 expression in human macrophages.

Beneficial effects of estrogen have been attributed to improved lipid profiles and to direct effects on the arterial wall. Macrophage-derived matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where they may contribute to plaque disruption. We have shown that oxidized low-density lipoprotein (Ox-LDL) increases matrix metalloproteinase-9 (MMP-9) expression in macrophages (Mφ).

Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/ beta-catenin and follistatin/transforming growth factor-beta signaling pathways.

Androgens are important regulators of body composition and promote myogenic differentiation and inhibit adipogenesis of mesenchymal, multipotent cells. Here, we investigated the mechanisms by which androgens induce myogenic differentiation of mesenchymal multipotent cells. Incubation of mesenchymal multipotent C3H 10T1/2 cells with testosterone and dihydrotestosterone promoted nuclear translocation of androgen receptor (AR)/beta-catenin complex and physical interaction of AR, beta-catenin, and T-cell factor-4 (TCF-4).