Supplementary Material for: Inhibitor of Differentiation 3, a Transcription Factor, Regulates Hyperlipidemia-Associated Kidney Disease

<p><b><i>Background:</i></b> Lipoprotein abnormalities are associated with a rapid decline in renal function in patients of chronic kidney disease. In addition, hyperlipidemia is associated with an increased risk of developing renal insufficiency. The underlying molecular mechanisms for these clinical findings are unclear. We have previously reported a role for inhibitor of differentiation 3 (ID3), a transcription factor, in regulating kidney disease in hyperlipidemia. Introducing a genetic deficiency of <i>Id3</i> in spontaneously hyperlipidemic apolipoprotein E knockout (<i>Apoe</i>^<i>-/-</i>) mice led to accelerated mesangioproliferative glomerulonephritis. The present study was carried out to further investigate the contribution of ID3 in hyperlipidemia-associated kidney disease. <b><i>Methods:</i></b> Female C57BL/6 mice that were ID3-sufficient wild-type (WT) or ID3-deficient (<i>Id3</i>^<i>-/-</i>) were fed a Western diet and evaluated for proteinuria, glomerular pathology, and immune infiltrating cells. Primary mesangial cell lines were generated from both mouse strains and stimulated with oxidized phospholipids. Cytokines and chemokines produced were measured by multiplex assays, ELISA, and QPCR. Glomerular isolates were studied for CXCL1 expression by QPCR. <b><i>Results:</i></b><i>Id3</i>^<i>-/-</i> mice on a Western diet developed accelerated proteinuria and mesangioproliferative glomerulonephritis compared to WT controls. In vitro, <i>Id3</i>^<i>-/-</i> glomerular mesangial cell lines produced higher levels of the monocyte chemoattractant CXCL1 in response to oxidized phospholipids. This was consistent with the rapid increase in glomerular CXCL1 expression followed by macrophage infiltration in <i>Id3</i>^<i>-/-</i> mice fed a Western diet. <b><i>Conclusions:</i></b> A functional ID3 influences susceptibility to kidney disease and prevents glomerular injury by regulating local chemokine production and inflammatory cell recruitment.</p

Interactions of amino acids with aluminum octacarboxyphthalocyanine hydroxide. Experimental and DFT studies

The influence of albumin and amino acids (l-serine, glycine, l-histidine, l-tryptophan, l-cysteine) on the properties of aluminum octacarboxyphthalocyanine hydroxide (Al(OH)PcOC) was investigated in a phosphate buffer (pH 8.0). Particular attention was paid to the spectroscopic properties and photostability of Al(OH)PcOC. The effect of albumin or amino acids on the photodegradation of Al(OH)PcOC was examined in water using red light: 685 nm and daylight irradiation. Analysis of kinetic curves indicated that interaction with those molecules increases the photostability of Al(OH)PcOC. The molecular structure of Al(OH)PcOC complexes (in vacuum and in water) with axially or equatorially coordinated amino acids was studied by the B3LYP/6-31G* method, and the effects on molecular structure and electronic absorption spectrum were investigated on the basis of the density functional theory. The calculation results revealed that axial coordination significantly reduces the non-planarity of the phthalocyanine ring, and, thus, alters the electronic structure. On the other hand, hydrogen bonding of phthalocyanine side COOH groups with amino acids, in equatorial complexes, does not change the structure within the center of the phthalocyanine, and causes only a slight increase in UV–vis bands intensity, which is in perfect agreement with experimental data. [Figure not available: see fulltext.

Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes

Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of α-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary α-cells and stimulated glucagon secretion. Pancreatic α-cell gp130 knockout (αgp130KO) mice showed no differences in glycemic control, α-cell function, or α-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, αgp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved α-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of α-cell gp130 receptor signaling has deleterious effects on α-cell function, promoting hyperglycemia. Antagonism of α-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes