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  • AZD8931 Our previous results revealed that in


    Our previous results revealed that, in podocytes, downregulation of AMPKα1 or AMPKα2 protein expression abolishes the stimulating effect of insulin on glucose uptake, suggesting that both isoforms play an important role in increasing glucose uptake in response to insulin stimulation. We demonstrated that one subunit is not sufficient to maintain insulin effects in podocytes when the second subunit is attenuated [21]. The current study confirmed our previous results, and we also demonstrated that metformin is able to increase glucose uptake into podocytes with downregulated AMPKα1 or AMPKα2 protein expression. We confirmed that SIRT1 downregulation results in the suppression of insulin action on glucose uptake into podocytes, and demonstrated that metformin treatment reverses this effect. Similar results were observed in SIRT1-depleted adipocytes. SIRT1 knockdown inhibited insulin-stimulated glucose transport, and treatment with activators of SIRT1 increased the insulin effect on glucose uptake [54]. Our previous study demonstrated that hyperglycemia increases the albumin permeability of podocytes due to activation of the Nox4 subunit of NADPH oxidase and dimerization of PKGIα in podocytes [24]. Because we demonstrated that SIRT1-AMPK crosstalk is involved in HG-dependent impairment of insulin responsiveness in podocytes [20], we examined the albumin permeability of podocytes in AZD8931 depleted of SIRT1 and showed that the decrease in SIRT1 protein levels in podocytes may contribute to increased albumin leakage through the glomerular filtration barrier observed in DN. Our results reveal that metformin treatment improved the glomerular filtration barrier tightness, decreasing the albumin permeability of podocytes with downregulated SIRT1 protein expression, which may be associated with restoration of the SIRT1 protein level and increase in its activity. SIRT1 activation by resveratrol was shown to attenuate DN, decreasing HG-induced VEGF expression in podocytes and its secretion in the cultured podocyte media, an effect that was attenuated by knocking down SIRT1 [55].
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    Introduction Down Syndrome (DS) is caused by the presence of an additional copy of human chromosome 21 and represents the most common human chromosomal anomaly. According to the website of the Global Down Syndrome Foundation (, there are an estimated 6 million people with DS worldwide. Cognitive impairments and congenital heart defects are the focus of most studies relating to the consequences of chromosome 21 trisomy in DS [1]. Immune dysfunctions however, also markedly affect the quality of life and health of individuals with DS. Suboptimal development and function of the DS immune system contribute to a higher incidence of autoimmune diseases, leukemia, and mostly respiratory tract infections. On the other hand, individuals with DS show a low incidence rate for solid tumors. Although it was originally hypothesized that the general phenomenon of precocious aging might underlie immune defects in DS [2], [3], evidence suggests that DS-specific and -intrinsic immune defects exist [4]. DS individuals exhibit disturbances in thymic development [5], and in the cellularity of the adaptive arm of immunity, including decreased numbers and functionality of T-lymphocytes [3], [6]. They also exhibit low B-lymphocyte numbers and a dysregulated Immunoglobulin pattern [7]. Increased levels of cytokines indicative of a pro-inflammatory profile, such as IFNγ, IL-6 and TNFα have also been documented in individuals with DS [8], [9], [10]. However, molecular mechanisms by which components of the immune responses might be affected in DS are not well characterized, particularly in the innate immune system. TRPM2 is a cationic channel activated by oxidative stress involved in the regulation of cytokine production. TRPM2 represents the unique fusion of a Ca-permeable pore of the Transient Receptor Potential (TRP)-family of ion channels with an enzymatic region that exhibits residual hydrolase-activity toward the phosphosugar ADP-ribose (ADPR) [11], [12]. We and other groups have shown that ADPR acts as a potent gating agent of TRPM2-channels [11] (Fig. 1). Conditions of stress, such as oxidant exposure as they occur in inflammatory environments, result in the depletion of the cellular DNA and NAD+ pools, leading to ADPR formation. Consequently, cells expressing recombinant TRPM2 were found to exhibit an H2O2-induced Ca-influx not seen in cells lacking the channel [13], [14]. As the Trpm2 gene is located on human chromosome 21 (21q22.3), we propose that its ion conducting activity might contribute to the immune phenotype observed in DS. In addition, the redox imbalance documented in DS might create an environment promoting the activation of the TRPM2 ion channel. Because TRPM2 is permeable to the universal second messenger Ca, this could result in altered signaling events and biological functions in cells expressing TRPM2, in particular innate immune cells.