Highlights d cGAS-STING activation and mitochondrial damage in tubules mediate acute kidney injury d cGAS-STING activation induces tubular inflammation and progression of AKI d Mitochondrial DNA leakage into the cytosol increased in AKIinduced tubular damage d Cytosolic mitochondrial DNA activates cGAS-STING signaling in tubular inflammation
Abstract,32-Microglobulin (#2M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis, a complication of long-term hemodialysis patients. Amyloid fibril proteins were isolated from connective tissues forming carpal tunnels in hemodialysis patients with carpal tunnel syndrome. Two-dimensional polyacrylamide gel electrophoresis and Western blotting demonstrated that most of the fl2M forming amyloid fibrils exhibited a more acidic pI value than normal ,B2M. This acidic /@2M was also found in a small fraction of f2M in sera and urine from these patients, whereas heterogeneity was not observed in healthy individuals. We purified acidic and normal iB2M from the urine of long-term hemodialysis patients and compared their physicochemical and immunochemical properties. Acidic ,62M, but not normal 6l2M, was brown in color and fluoresced, both of which are characteristics of advanced glycation end products (AGEs) of the Maillard reaction. Immunochemical studies showed that acidic #2M reacted with anti-AGE antibody and also with an antibody against an Amadori product, an early product of the Maillard reaction, but normal f2M did not react with either antibody. Incubating normal I2M with glucose in vitro resulted in a shift to a more acidic pI, generation of fluorescence, and immunoreactivity to the anti-AGE antibody. The #2M forming amyloid fibrils also reacted with anti-AGE antibody. These data provided evidence that AGE-modified
Abstract. The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N ⑀ -carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre-and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action.Advanced glycation and oxidation irreversibly modify proteins over the years and thus contribute to aging phenomena (1). Their local or generalized acceleration is associated with atherosclerosis (2-6) as well as with various diabetic (7-10) and uremic complications (11-13). Inhibition of advanced glycation end products (AGE) formation has thus become a therapeutic goal.Aminoguanidine, the first AGE inhibitor discovered in 1986 (14), and (Ϯ)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) (15) are both hydrazine-derivatives. They inhibit in vitro the formation of AGE, pentosidine (16), and N ⑀ -carboxymethyllysine (CML) (17) from a variety of individual precursors, such as ribose, glucose, and ascorbate, as well as that of advanced lipoxidation end products (ALE), malondialdehyde-lysine and 4-hydroxynonenal-protein adduct (18), from arachidonate (19). They also inhibit pentosidine generation in diabetic and uremic plasma incubated for 4 wk (20).As expected, both compounds correct several biologic effects that are associated with AGE formation. In murine thymocyte and fibroblasts, they inhibit the phosphorylation of tyrosine residues of a number of intracellular proteins induced by cell surface Schiff base formation (21). Given to diabetic animal models, such as Otsuka-Long-Evans-Tokushima-Fatty (OLETF) or streptozotocin-treated rats, they reduce urinary albumin excretion and improve glomerular morphology (15,22). Oral admi...
Background: A severe adverse reaction to sulfasalazine therapy has been associated with hypersensitivity syndrome, the clinical features of which are similar to infectious mononucleosis. No serologic evidence of viral infections has been reported with this syndrome; however, human herpesvirus 6 infection has not been specifically investigated, which could cause an infectious mononucleosislike syndrome.Observations: We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine. The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. Clinical signs included a maculopapular rash progressing to exfoliative eryth-roderma, fever, and lymphadenopathy. Leukocytosis, atypical lymphocytes, liver dysfunction, and renal disturbance were also observed. In 1 patient, human herpesvirus 6 variant B was isolated from peripheral blood mononuclear cells, and in both patients anti-human herpesvirus 6 IgG titers increased considerably.Conclusions: Two cases of hypersensitivity syndrome due to sulfasalazine use were associated with the reactivation of human herpesvirus 6, which may be a required cause of hypersensitivity syndrome.
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