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1.  S100/calgranulin-mediated inflammation accelerates left ventricular hypertrophy and aortic valve sclerosis in chronic kidney disease in a RAGE dependent manner 
S100A12 and fibroblast growth factor 23 (FGF23) are biomarkers of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD.
Approach and Results
A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mouse (hBAC-S100) to generate a novel humanized mouse model. CKD was induced by ureteral ligation and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased FGF 23 in the hearts, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking the receptor for advanced glycation endproducts (RAGE) with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNFα, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts.
Myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic dysfunction in hBAC-S100 mice with CKD.
PMCID: PMC4108264  PMID: 24855059
S100 proteins; RAGE; chronic kidney disease; LVH; ectopic cardiac calcification
2.  Contrasting Effects of Systemic Monocyte/Macrophage and CD4+ T Cell Depletion in a Reversible Ureteral Obstruction Mouse Model of Chronic Kidney Disease 
Using a reversible UUO model (rUUO), we have demonstrated that C57BL/6 mice are susceptible to development of CKD after obstruction-mediated kidney injury while BALB/c mice are resistant. We hypothesized that selective systemic depletion of subpopulations of inflammatory cells during injury or repair might alter the development of CKD. To investigate the impact of modification of Th-lymphocytes or macrophage responses on development of CKD after rUUO, we used an anti-CD4 antibody (GK1.5) or liposomal clodronate to systemically deplete CD4+ T cells or monocyte/macrophages, respectively, prior to and throughout the rUUO protocol. Flow cytometry and immunohistochemistry confirmed depletion of target cell populations. C57BL/6 mice treated with the GK1.5 antibody to deplete CD4+ T cells had higher BUN levels and delayed recovery from rUUO. Treatment of C57BL/6 mice with liposomal clodronate to deplete monocyte/macrophages led to a relative protection from CKD as assessed by BUN values. Our results demonstrate that modulation of the inflammatory response during injury and repair altered the susceptibility of C57BL/6 mice to development of CKD in our rUUO model.
PMCID: PMC3892942  PMID: 24489579
3.  Vascular Remodeling and Arterial Calcification Are Directly Mediated by S100A12 (EN-RAGE) in Chronic Kidney Disease 
American Journal of Nephrology  2011;33(3):250-259.
The proinflammatory cytokine S100A12 (also known as EN-RAGE) is associated with cardiovascular morbidity and mortality in hemodialysis patients. In the cur- rent study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in nonatherosclerosis-prone C57BL/6J mice on normal rodent chow diet, but exposed to the metabolic changes of chronic kidney disease (CKD), would develop vascular disease resembling that observed in patients with CKD.
CKD was induced in S100A12 transgenic mice and wild-type littermate mice not expressing human S100A12 by surgical ligation of the ureters. The aorta was analyzed after 7 weeks of elevated BUN (blood urea nitrogen), and cultured aortic smooth muscle cells were studied.
We found enhanced vascular medial calcification in S100A12tg mice subjected to CKD. Vascular calcification was mediated, at least in part, by activation of the receptor for S100A12, RAGE (receptor for advanced glycation endproducts), and by enhanced oxidative stress, since inhibition of NADPH-oxidase Nox1 and limited access of S100A12 to RAGE attenuated the calcification and gene expression of osteoblastic genes in cultured vascular smooth muscle cells.
S100A12 augments CKD-triggered osteogenesis in murine vasculature, reminiscent of features associated with enhanced vascular calcification in patients with chronic and end-stage kidney disease.
PMCID: PMC3064943  PMID: 21372560
Chronic kidney disease; Blood urea nitrogen; Receptor for advanced glycation endproducts
4.  Increase in Group G Streptococcal Infections in a Community Hospital, New York, USA 
Emerging Infectious Diseases  2009;10(6):1455-60.
PMCID: PMC2727315  PMID: 19523319
Streptococci; group G streptococci; hospital; New York; USA; letter

Results 1-4 (4)