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Beta 2 adrenergic receptor (β2-AR)-agonists, widely used as bronchodilators, have demonstrated wide-spectrum anti-inflammatory properties in both immune and non-immune cells in various tissues. Their anti-inflammatory properties are mediated primarily, but not exclusively, via activation of the canonical β2-AR signaling pathway (β2-AR/cAMP/PKA). As non-canonical β2-AR signaling also occurs, several inconsistent findings on the anti-inflammatory effect of β2-agonists are notably present. Increasing amounts of evidence have unveiled the alternative mechanisms of the β2-AR agonists in protecting the tissues against injuries, i.e., by augmenting mitochondria biogenesis and SIRT1 activity, and by attenuating fibrotic signaling. This review mainly covers the basic mechanisms of the anti-inflammatory effects of β2-AR activation along with its limitations. Specifically, we summarized the role of β2-AR signaling in regulating kidney function and in mediating the progression of acute and chronic kidney diseases. Given their versatile protective effects, β2-agonists can be a promising avenue in the treatment of kidney diseases. [ABSTRACT FROM AUTHOR]

Truncated 4′-thionucleosides 1–4 and 4′-oxonucleosides 5–8 as potent and selective A3AR antagonists were synthesized from d-mannose and d-erythronic acid γ-lactone, respectively. These nucleosides were evaluated for their anti-fibrotic renoprotective activity in TGF-β1-treated murine proximal tubular (mProx) cells. Their antagonistic activities for A3AR were proportional to their inhibitory activities against TGF-β1-induced collagen I upregulation in mProx cells. This result suggests that the binding affinity of A3AR antagonists is closely correlated with their anti-fibrotic activity. Thus, A3AR antagonists might be novel therapeutic candidates for treating chronic kidney disease. [ABSTRACT FROM AUTHOR]

Hydrogen peroxide (H2O2) produced endogenously can cause mitochondrial dysfunction and metabolic complications in various cell types by inducing oxidative stress. In the liver, oxidative and endoplasmic reticulum (ER) stress affects the development of non-alcoholic fatty liver disease (NAFLD). Although a link between both stresses and fatty liver diseases has been suggested, few studies have investigated the involvement of catalase in fatty liver pathogenesis. We examined whether catalase is associated with NAFLD, using catalase knockout (CKO) mice and the catalase-deficient human hepatoma cell line HepG2. Hepatic morphology analysis revealed that the fat accumulation was more prominent in high-fat diet (HFD) CKO mice compared to that in age-matched wild-type (WT) mice, and lipid peroxidation and H2O2 release were significantly elevated in CKO mice. Transmission electron micrographs indicated that the liver mitochondria from CKO mice tended to be more severely damaged than those in WT mice. Likewise, mitochondrial DNA copy number and cellular ATP concentrations were significantly lower in CKO mice. In fatty acid-treated HepG2 cells, knockdown of catalase accelerated cellular lipid accumulation and depressed mitochondrial biogenesis, which was recovered by co-treatment with N-acetyl cysteine or melatonin. This effect of antioxidant was also true in HFD-fed CKO mice, suppressing fatty liver development and improving hepatic mitochondrial function. Expression of ER stress marker proteins and hepatic fat deposition also increased in normal-diet, aged CKO mice compared to WT mice. These findings suggest that H2O2 production may be an important event triggering NAFLD and that catalase may be an attractive therapeutic target for preventing NAFLD. [ABSTRACT FROM AUTHOR]

Fibrosis of epithelial parenchymal organs and end-stage organ failure, the final common pathway of many progressive chronic diseases including chronic kidney disease, continue to increase worldwide and are a major determinant of morbidity and mortality. Fibrosis is an active biosynthetic healing response initiated to protect the tissue from injury through the timed release of proteins but leads to serious tissue damage when it becomes independent from the initiating stimulus. Massive deposition of extracellular matrix by accumulation of myofibroblasts and disruption of the normal tissue architecture are characteristic of tissue fibrosis. The highly conserved Wnt/β-catenin signaling pathway is essential to embryonic development in general and kidney morphogenesis in particular by regulating the expression of target genes, most often through the transcription factor T cell factor (TCF) and/or lymphoid enhancer factor (LEF). Emerging evidence from studies of renal fibrosis suggests that altered Wnt/β-catenin signaling is linked to the pathogenesis of renal fibrosis. The renoprotective properties of some currently available drugs might be attributable in part to inhibition of Wnt signaling. The development of orally active Wnt modulators will provide a potentially important pharmacological tool for further investigating the role of Wnt/β-catenin signaling and might offer a novel therapeutic strategy in renal fibrosis. [ABSTRACT FROM AUTHOR]

Purpose. There is still no reliable method of preventing or treating chronic rejection or transplant vascular sclerosis. A recent in vitro cell culture study showed that carvedilol significantly inhibited the proliferation of vascular smooth muscle cells (VSMCs); however, the effect of carvedilol in the presence of cyclosporine (CsA) has not yet been reported. Using in vitro cultured VSMCs, we measured the antiproliferative activity of carvedilol alone and in combination with CsA. Methods. Growth-arrested cultured VSMCs from the thoracic aorta of Sprague-Dawley rats were exposed to platelet-derived growth factor (PDGF)-BB, endothelin (ET)-I, and angiotensin (ANG)-II. Carvedilol (1 and 10 μM) and/or CsA (100 nM) were added as test drugs. DNA synthesis was assessed by measuring the incorporated [3H]thymidine activity, and the percentage of inhibition in the presence of the test drugs was determined. Results. Compared with the PDGF-stimulated control, DNA synthesis decreased significantly to 60.3% ± 10.4% and 18.3% ± 5.9% in the presence of 1 and 10 μM of carvedilol, respectively ( P < 0.05, each). Carvedilol significantly inhibited the activity of VSMCs stimulated by ET-1 and ANG-II. The IC50 of carvedilol was 1–10 μM. CsA only inhibited VSMCs significantly in the PDGF-stimulated subgroup. The addition of CsA in the presence of carvedilol did not affect the inhibitory activity of carvedilol. The pattern of inhibition in the combined group was uniform and similar to that of the carvedilol alone group, regardless of the stimulator used. Conclusion. Carvedilol significantly inhibited the DNA synthesis of VSMCs regardless of the kind of stimulators examined, even in the presence of CsA. These results indicate that carvedilol has the unique potential to inhibit the development of transplant vascular sclerosis in hypertensive transplant recipients under CsA-based immunosuppression. [ABSTRACT FROM AUTHOR]

Oxidative stress has been known to play an important role in the development and progression of diabetic nephropathy, but the intracellular signal transduction pathways regulated by reactive oxygen species (ROS) have not been clearly defined. High glucose (HG) induces intracellular ROS directly via glucose metabolism and auto-oxidation and indirectly through the formation of advanced glycation end products and their receptor binding. ROS mimic the stimulatory effects of HG and upregulate transforming growth factor-beta 1, plasminogen activator inhibitor-1, and extracellular matrix (ECM) proteins by glomerular mesangial cells, thus leading to mesangial expansion. ROS activate other signaling molecules, such as protein kinase C and mitogen-activated protein kinases and transcription factors, such as nuclear factor-kappa B, activator protein-1, and specificity protein 1 leading to transcription of genes encoding cytokines, growth factors, and ECM proteins. Finally, various antioxidants inhibit mesangial cell activation by HG and ameliorate features of diabetic nephropathy. These findings qualify ROS as intracellular messengers and as integral glucose-signaling molecules in glomerular mesangial cells in diabetic nephropathy. With this new concept, ROS assume a greater importance in the pathogenesis of diabetic nephropathy. Future studies elucidating other downstream-signaling molecules activated by ROS in mesangial and other renal cells will allow us to understand the final cellular responses to HG, such as proliferation, differentiation, apoptosis, and ECM accumulation. With this new information, we should be able to develop strategies for a more rational treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the role of the proximal tubule in microalbuminuria in the early stage of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (50 mg/kg, i.v.). After 2 weeks, albumin delivery in the proximal tubule was measured using micropuncture and the endocytosis process of FITC-labeled albumin was evaluated with immunoelectron microscopy. Albumin was significantly reabsorbed in the proximal convoluted tubule (PCT) of controls (0.39±0.05 ng/min at early PCT to 0.17±0.08 at late PCT, P<0.05), whereas albumin reabsorption was inhibited in diabetic rats (0.27±0.05 to 0.21±0.08). Immunogold study revealed that FITC-albumin was significantly less reabsorbed in endosomes and lysosomes of S1 segments in diabetic rats than in controls (endosome: 1.20±0.10 vs 2.16±0.15 µm–1, P<0.0001; lysosome: 0.26±0.03 vs 0.83±0.07, P<0.0001). The expression of megalin, an endocytosis receptor, was decreased at the apical membrane of PCT in diabetic rats. The lipid peroxidation production in the proximal tubule was significantly increased in diabetic rats. In conclusion, albuminuria in early-stage diabetic rats can be partly explained by a decreased albumin endocytosis with reduced megalin expression and with increased lipid peroxidation in the proximal tubule. [ABSTRACT FROM AUTHOR]

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) have similar initial histological findings; however, their prognoses are distinct. Therefore, it is of great importance to discriminate FSGS from MCD in the early phase of disease and predict clinical prognosis. A discovery set of 184 urine samples (61 healthy control, 80 MCD, and 43 FSGS) and a validation set of 61 urine samples (12 healthy control, 26 MCD, and 23 FSGS) were collected at the time of kidney biopsy. Metabolic profiles were examined using nuclear magnetic resonance spectroscopy. Of 70 urinary metabolites, myo-inositol was significantly higher in FSGS patients than in control patients (discovery set, 2.34-fold, P < 0.001; validation set, 2.35-fold, P = 0.008) and MCD patients (discovery set, 2.48-fold, P = 0.002; validation set, 1.69-fold, P = 0.042). Myo-inositol showed an inverse relationship with the initial estimated glomerular filtration rate (eGFR) and was associated with the plasma level of soluble urokinase-type plasminogen activator receptor in FSGS patients. Myo-inositol treatment ameliorated the decreased expression of ZO-1 and synaptopodin in an in vitro FSGS model, and as myo-inositol increased, myo-inositol oxygenase tissue expression decreased proportionally to eGFR. Furthermore, urinary myo-inositol exhibited an increase in the power to discriminate FSGS patients, and its addition could better predict the response to initial treatment. In conclusion, urinary myo-inositol may be an important indicator in the diagnosis and treatment of FSGS patients. [ABSTRACT FROM AUTHOR]

Long-term peritoneal dialysis is associated with progressive fibrosis of the peritoneum. Epithelial-mesenchymal transition (EMT) of mesothelial cells is an important mechanism involved in peritoneal fibrosis, and TGF-β1 is considered central in this process. However, targeting currently known TGF-β1-associated pathways has not proven effective to date. Therefore, there are still gaps in understanding the mechanisms underlying TGF-β1-associated EMT and peritoneal fibrosis. We conducted network-based integrated analysis of transcriptomic and proteomic data to systemically characterize the molecular signature of TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs). To increase the power of the data, multiple expression datasets of TGF-β1-stimulated human cells were employed, and extended based on a human functional gene network. Dense network sub-modules enriched with differentially expressed genes by TGF-β1 stimulation were prioritized and genes of interest were selected for functional analysis in HPMCs. Through integrated analysis, ECM constituents and oxidative stress-related genes were shown to be the top-ranked genes as expected. Among top-ranked sub-modules, TNFAIP6, ZC3H12A, and NNT were validated in HPMCs to be involved in regulation of E-cadherin, ZO-1, fibronectin, and αSMA expression. The present data shows the validity of network-based integrated analysis in discovery of novel players in TGF-β1-induced EMT in peritoneal mesothelial cells, which may serve as new prognostic markers and therapeutic targets for peritoneal dialysis patients. [ABSTRACT FROM AUTHOR]

The 50 kDa glycoprotein plasminogen activator inhibitor 1 (PAI-1) is the major physiological inhibitor of tissue-type and urokinase-type plasminogen activator. These two molecules convert inactive plasminogen into its fibrin-degrading form, plasmin. Plasma and tissue concentrations of PAI-1 are extremely low under normal circumstances but increase under pathologic conditions. This increase is mediated by many factors, including reactive oxygen species. Increased PAI-1 activity is associated with an increased risk of ischemic cardiovascular events and tissue fibrosis. Whereas the antifibrinolytic property of PAI-1 derives mainly from its inhibition of serine proteases, its profibrotic actions seem to derive from a capacity to stimulate interstitial macrophage recruitment and increase transcription of profibrotic genes, as well as from inhibition of serine proteases. Despite studies in mice that lack or overexpress PAI-1, the biological effects of this molecule in humans remain incompletely understood because of the complexity of the PAI-1-plasminogen-activator-plasmin system. The cardioprotective and renoprotective properties of some currently available drugs might be attributable in part to inhibition of PAI-1. The development of an orally active, high-affinity PAI-1 inhibitor will provide a potentially important pharmacological tool for further investigation of the role of PAI-1 and might offer a novel therapeutic strategy in renal and cardiovascular diseases. [ABSTRACT FROM AUTHOR]