Nephrology Research and Training Center
Nephrology Research and Training Center
Kanbay M.,Fatih University |
Chen Y.,Nephrology Research and Training Center |
Chen Y.,University of Alabama at Birmingham |
Solak Y.,Selcuk University |
And 2 more authors.
Current Opinion in Nephrology and Hypertension | Year: 2011
Purpose of review: Investigation into the underlying mechanisms of salt sensitivity has made important advances in recent years. This review examines in particular the effects of sodium and potassium on vascular function. Recent findings: Sodium chloride (salt) intake promotes cutaneous lymphangiogenesis mediated through tissue macrophages and directly alters endothelial cell function, promoting increased production of transforming growth factor-β (TGF-β) and nitric oxide. In the setting of endothelial dysfunction, such as occurs with aging, diminished nitric oxide production exacerbates the vascular effects of TGF-b, promoting decreased arterial compliance and hypertension. Dietary potassium intake may serve as an important countervailing influence on the effects of salt in the vasculature. Summar: There is growing appreciation that, independently of alterations in blood pressure, dietary intake of sodium and potassium promotes functional changes in the vasculature and lymphatic system. These changes may protect against development of saltsensitive hypertension. While salt sensitivity cannot be ascribed exclusively to these factors, perturbation of these processes promotes hypertension during high-salt intake. These studies add to the list of genetic and environmental factors that are associated with salt sensitivity, but in particular provide insight into adaptive mechanisms during high salt intake. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Deshane J.,Nephrology Research and Training Center |
Deshane J.,University of Alabama at Birmingham |
Kim J.,Nephrology Research and Training Center |
Kim J.,University of Alabama at Birmingham |
And 6 more authors.
Journal of Biological Chemistry | Year: 2010
HO-1 (heme oxygenase-1) is an inducible microsomal enzyme that catalyzes the degradation of pro-oxidant heme. The goal of this study was to characterize a minimal enhancer region within the human HO-1 gene and delineate its role in modulating HO-1 expression by participation with its promoter elements in renal epithelial cells. Deletion analysis and site-directed mutagenesis identified a 220-bp minimal enhancer in intron 1 of the HO-1 gene, which regulates hemin-mediated HO-1 gene expression. Small interfering RNA, decoy oligonucleotides, site-directed mutagenesis, and chromatin immunoprecipitation assays confirmed the functional interaction of Sp1 with a consensus binding sequence within the 220-bp region. Mutations of regulatory elements within the -4.5 kb promoter region (a cyclic AMP response and a downstream NF-E2/AP-1 element, both located at -4.0 kb, and/or an E-box sequence located at -44 bp) resulted in the loss of enhancer activity. A chromosome conformation capture assay performed in human renal epithelial (HK-2) cells demonstrated hemin-inducible chromatin looping between the intronic enhancer and the -4.0 kb promoter region in a time-dependent manner. Restriction digestion with ApaLI (which cleaves the 220-bp enhancer) led to a loss of stimulus-dependent chromatin looping. Sp1 small interfering RNA and mithramycin A, a Sp1 binding site inhibitor, resulted in loss of the loop formation between the intronic enhancer and the distal HO-1 promoter by the chromosome conformation capture assay. These results provide novel insight into the complex molecular interactions that underlie human HO-1 regulation in renal epithelial cells. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Ying W.-Z.,Nephrology Research and Training Center |
Ying W.-Z.,University of Alabama at Birmingham |
Aaron K.J.,Nephrology Research and Training Center |
Aaron K.J.,University of Alabama at Birmingham |
And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2014
The amount of Na+ and K+ in the diet promotes significant changes in endothelial cell function. In the present study, a series of in vitro and in vivo experiments determined the role of Na+ and K+ in the regulation of two pleckstrin homology domain-containing intracellular signaling molecules, phospholipase C (PLC)-γ1 and epithelial and endothelial tyrosine kinase/bone marrow tyrosine kinase on chromosome X (Bmx), and agonist-generated Ca2+ signaling in the endothelium. Extracellular K+ concentration regulated the levels of activated PLC-γ1, Bmx, and carbachol-stimulated intracellular Ca2+ mobilization in human endothelial cells. Additional experiments confirmed that high-conductance Ca2+-activated K+ channels and phosphatidylinositol 3-kinase mediated these effects. The content of Na+and K+ in the diet also regulated Bmx levels in endothelial cells and activated PLC-γ1 levels in rats in vivo. The effects of dietary K+ on Bmx were more pronounced in rats fed a high-salt diet compared with rats fed a low-salt diet. These experiments elucidated an endothelial cell signaling mechanism regulated by electrolytes, further demonstrating an integral relationship between endothelial cell function and dietary Na+ and K+ content. © 2014 the American Physiological Society.
PubMed | Nephrology Research and Training Center and University of Alabama at Birmingham
Type: Journal Article | Journal: Journal of the American Society of Nephrology : JASN | Year: 2015
Renal ischemia-reperfusion injury is mediated by a complex cascade of events, including the immune response, that occur secondary to injury to renal epithelial cells. We tested the hypothesis that heme oxygenase-1 (HO-1) expression, which is protective in ischemia-reperfusion injury, regulates trafficking of myeloid-derived immune cells in the kidney. Age-matched male wild-type (HO-1(+/+)), HO-1-knockout (HO-1(-/-)), and humanized HO-1-overexpressing (HBAC) mice underwent bilateral renal ischemia for 10 minutes. Ischemia-reperfusion injury resulted in significantly worse renal structure and function and increased mortality in HO-1(-/-) mice. In addition, there were more macrophages (CD45(+) CD11b(hi)F4/80(lo)) and neutrophils (CD45(+) CD11b(hi) MHCII(-) Gr-1(hi)) in HO-1(-/-) kidneys than in sham and HO-1(+/+) control kidneys subjected to ischemia-reperfusion. However, ischemic injury resulted in a significant decrease in the intrarenal resident dendritic cell (DC; CD45(+)MHCII(+)CD11b(lo)F4/80(hi)) population in HO-1(-/-) kidneys compared with controls. Syngeneic transplant experiments utilizing green fluorescent protein-positive HO-1(+/+) or HO-1(-/-) donor kidneys and green fluorescent protein-negative HO-1(+/+) recipients confirmed increased migration of the resident DC population from HO-1(-/-) donor kidneys, compared to HO-1(+/+) donor kidneys, to the peripheral lymphoid organs. This effect on renal DC migration was corroborated in myeloid-specific HO-1(-/-) mice subjected to bilateral ischemia. These mice also displayed impaired renal recovery and increased fibrosis at day 7 after injury. These results highlight an important role for HO-1 in orchestrating the trafficking of myeloid cells in AKI, which may represent a key pathway for therapeutic intervention.