New pathways to renal damage: Role of ADMA in retarding renal disease progression
Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. Journal of nephrology
(Impact Factor: 1.45).
In recent years, increasing evidence has been found that chronic kidney disease (CKD) is a strong cardiovascular risk factor, and therefore, the concept of cardiorenal association is well recognized. One possible factor that could explain this link seems to be endothelial dysfunction. It is widely recognized that endothelial dysfunction plays important roles in both the initiation and progression of atherosclerosis. In addition, we have come to understand that endothelial dysfunction may be a causative factor for proteinuria and/or progression of CKD. Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue found in plasma and various types of tissues, acting as an endogenous nitric oxide synthase inhibitor in vivo. Plasma levels of ADMA are elevated in patients with CKD and have been found to be a strong biomarker or predictor for future cardiovascular disease (CVD) as well as the progression of renal injury. These findings suggest that elevation of ADMA-mediated endothelial dysfunction may be a missing link between CVD and CKD. In this review, we discuss the biology of ADMA, especially focusing on its role in the progression of CKD.
Available from: John F Bertram
- "In patients, eNOS polymorphisms that lead to decreased eNOS expression and activity have been associated with advanced DN and progressive IgA nephropathy –. Scavengers of endothelial nitric oxide (NO)-production, such as asymmetric dimethyl-arginine or N-Nitro-L-Arginine Methyl Ester (L-NAME) can acutely increase glomerular permeability and induce proteinuria –. Collectively, these studies suggest that endothelial dysfunction is involved in the development of diabetic and non-diabetic glomerular injury and renal fibrosis , . "
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ABSTRACT: The role of podocytes in the development and progression of glomerular disease has been extensively investigated in the past decade. However, the importance of glomerular endothelial cells in the pathogenesis of proteinuria and glomerulosclerosis has been largely ignored. Recent studies have demonstrated that endothelial nitric oxide synthatase (eNOS) deficiency exacerbates renal injury in anti-GBM and remnant kidney models and accelerates diabetic kidney damage. Increasing evidence also demonstrates the importance of the glomerular endothelium in preventing proteinuria. We hypothesize that endothelial dysfunction can initiate and promote the development and progression of glomerulopathy. Administration of adriamycin (ADR) to C57BL/6 mice, normally an ADR resistant strain, with an eNOS deficiency induced overt proteinuria, severe glomerulosclerosis, interstitial fibrosis and inflammation. We also examined glomerular endothelial cell and podocyte injury in ADR-induced nephropathy in Balb/c mice, an ADR susceptible strain, by immunostaining, TUNEL and Western blotting. Interestingly, down-regulation of eNOS and the appearance of apoptotic glomerular endothelial cells occurred as early as 24 hours after ADR injection, whilst synaptopodin, a functional podocyte marker, was reduced 7 days after ADR injection and coincided with a significant increase in the number of apoptotic podocytes. Furthermore, conditioned media from mouse microvascular endothelial cells over-expressing GFP-eNOS protected podocytes from TNF-α-induced loss of synaptopodin. In conclusion, our study demonstrated that endothelial dysfunction and damage precedes podocyte injury in ADR-induced nephropathy. Glomerular endothelial cells may protect podocytes from inflammatory insult. Understanding the role of glomerular endothelial dysfunction in the development of kidney disease will facilitate in the design of novel strategies to treat kidney disease.
Available from: Theodoros Dimitroulas
- "After proteolysis of methylated nuclear proteins, free dimethylarginines are released by the cells. PRMT I catalyzes asymmetrical dimethylation and monomethylation of arginine residues and produces ADMA, whereas type II catalyzes symmetrical dimethylation and monomethylasion and forms symmetric dimethylarginine—the biologically inactive stereoisomer of ADMA . Free circulating ADMA is then released after degradation of such methylated protein residues. "
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ABSTRACT: The last few decades have witnessed an increased life expectancy of patients suffering with systemic rheumatic diseases, mainly due to improved management, advanced therapies and preventative measures. However, autoimmune disorders are associated with significantly enhanced cardiovascular morbidity and mortality not fully explained by traditional cardiovascular disease (CVD) risk factors. It has been suggested that interactions between high-grade systemic inflammation and the vasculature lead to endothelial dysfunction and atherosclerosis, which may account for the excess risk for CVD events in this population. Diminished nitric oxide synthesis-due to down regulation of endothelial nitric oxide synthase-appears to play a prominent role in the imbalance between vasoactive factors, the consequent impairment of the endothelial hemostasis and the early development of atherosclerosis. Asymmetric dimethylarginine (ADMA) is one of the most potent endogenous inhibitors of the three isoforms of nitric oxide synthase and it is a newly discovered risk factor in the setting of diseases associated with endothelial dysfunction and adverse cardiovascular events. In the context of systemic inflammatory disorders there is increasing evidence that ADMA contributes to the vascular changes and to endothelial cell abnormalities, as several studies have revealed derangement of nitric oxide/ADMA pathway in different disease subsets. In this article we discuss the role of endothelial dysfunction in patients with rheumatic diseases, with a specific focus on the nitric oxide/ADMA system and we provide an overview on the literature pertaining to ADMA as a surrogate marker of subclinical vascular disease.
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ABSTRACT: Preeclampsia, a pregnancy-specific hypertensive syndrome, is one of the leading causes of premature births as well as fetal and maternal death. Preeclampsia lacks effective therapies because of the poor understanding of disease pathogenesis. The aim of this paper is to review molecular signaling pathways that could be responsible for the pathogenesis of preeclampsia.
This article reviews the English-language literature for pathogenesis and pathophysiological mechanisms of preeclampsia based on genome-wide gene expression profiling and proteomic studies.
We show that the expression of the genes and proteins involved in response to stress, host-pathogen interactions, immune system, inflammation, lipid metabolism, carbohydrate metabolism, growth and tissue remodeling was increased in preeclampsia. Several significant common pathways observed in preeclampsia overlap the datasets identified in TLR (Toll-like receptor)- and RAGE (receptor for advanced glycation end products)-dependent signaling pathways. Placental oxidative stress and subsequent chronic inflammation are considered to be major contributors to the development of preeclampsia.
This review summarizes recent advances in TLR- and RAGE-mediated signaling and the target molecules, and provides new insights into the pathogenesis of preeclampsia.
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