Edited by Xiao-Fan WangPodocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. miR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a
Sinus venosus atrial septal defect (SVASD) is a rare adult congenital heart disease which permits shunting of blood from the systemic to the pulmonary circulation and is commonly associated with anomalous pulmonary venous return.We report a case of a 27-year-old man with a history of premature birth and unilateral cryptorchidism who was admitted for syncope. Electrocardiogram (ECG) demonstrated atrial fibrillation (AF)and S1Q3T3 pattern along with an incomplete right bundle branch block. Transthoracic echocardiography (TTE) suggested the presence of right ventricular pressure and volume overload and severe right ventricular and right atrial enlargement. The agitated saline study was negative suggesting no inter-atrial communication. Transesophageal echocardiography (TEE) demonstrated a superior SVASD and raised the possibility of an anomalous pulmonary venous connection. Chest computed tomography identified the right superior pulmonary vein connection to the superior vena cava.The diagnosis of SVASD poses multiple challenges from the variety of symptoms to the selection of appropriate imaging and the complexity of surgical treatment.
Genetic variations in the ITGAM gene (coding for CD11b) produce defective CD11b and associate with a risk for systemic lupus erythematosus (SLE, lupus). Elevated level of IFN I in circulation plays a pathogenic role and is a heritable risk factor for SLE. Whether variations in ITGAM are linked to high IFN I and whether CD11b activation could be a therapeutic strategy is unknown and is explored here. We measured serum IFN I activity in 171 SLE patients and report that three ITGAM variants significantly associate with elevated levels of IFN I in lupus, suggesting a direct link between reduced CD11b activity and elevated inflammation in patients. Given that ITGAM SNPs result in functionally deficient CD11b, we tested whether partial CD11b activation with small molecule agonist, leukadherin-1 (LA1) reduces IFN I responses and determined the underlying mechanistic pathways. CD11b activation with LA1 reduced TLR-dependent pro-inflammatory signaling in leukocytes and suppressed IFN I signaling via an AKT-FOXO3-IRF7 pathway. TLR-stimulated macrophages from CD11b SNP carriers showed increased basal expression of IRF7 and IFNB, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1. To test the efficacy of LA1 in vivo, we used the MRL/lpr mice that develop IFN I-dependent multi-organ lupus. LA1 treatment reduced IFN I responses and protected lupus-prone MRL/lpr mice from kidney injury. LA1-treated mice had reduced proteinuria, IgG renal immune complex deposition, and glomerular damage as compared to controls. LA1 suppresses TLR-stimulated overproduction of cytokines in vivo, which drives lupus pathogenesis. These findings suggest that pharmacological CD11b activation is a promising therapeutic strategy in human SLE.
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