It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-β1 (TGF- β1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop−/− mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.

IntroductionA potential independent association was recently demonstrated between high red blood cell distribution width (RDW) and the risk of all-cause mortality in critically ill patients, although the mechanism underlying this relationship remains unclear. Little is known about the impact changes in RDW may have on survival in critically ill patients. Therefore, we investigated the prognostic significance of changes in RDW during hospital stay in patients with severe sepsis or septic shock.MethodsWe prospectively enrolled 329 patients who were admitted to the emergency department (ED) and received a standardized resuscitation algorithm (early-goal directed therapy) for severe sepsis or septic shock. The relationship between the changes in RDW during the first 72 hours after ED admission and all-cause mortality (28-day and 90-day) were analyzed by categorizing the patients into four groups according to baseline RDW value and ΔRDW72hr-adm (RDW at 72 hours – RDW at baseline).ResultsThe 28-day and 90-day mortality rates were 10% and 14.6%, respectively. Patients with increased RDW at baseline and ΔRDW72hr-adm >0.2% exhibited the highest risks of 28-day and 90-day mortality, whereas the patients with normal RDW level at baseline and ΔRDW72hr-adm ≤0.2% (the reference group) had the lowest mortality risks. For 90-day mortality, a significantly higher mortality risk was observed in the patients whose RDW increased within 72 hours of ED admission (normal RDW at baseline and ΔRDW72hr-adm >0.2%), compared to the reference group. These associations remained unaltered even after adjusting for age, sex, Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index, renal replacement therapy, albumin, hemoglobin, lactate, C-reactive protein and infection sites in multivariable models.ConclusionsWe found that an increase in RDW from baseline during the first 72 hours after hospitalization is significantly associated with adverse clinical outcomes. Therefore, a combination of baseline RDW value and an increase in RDW can be a promising independent prognostic marker in patients with severe sepsis or septic shock.

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IntroductionMean platelet volume (MPV) is suggested as an index of inflammation, disease activity, and anti-inflammatory treatment efficacy in chronic inflammatory disorders; however, the effect of MPV on sepsis mortality remains unclear. Therefore, we investigated whether the change in MPV between hospital admission and 72 hours (ΔMPV72h-adm) predicts 28-day mortality in severe sepsis and/or septic shock.MethodsWe prospectively enrolled 345 patients admitted to the emergency department (ED) who received standardized resuscitation (early goal-directed therapy) for severe sepsis and/or septic shock between November 2007 and December 2011. Changes in platelet indices, including ΔMPV72h-adm, were compared between survivors and non-survivors by linear mixed model analysis. The prognostic value of ΔMPV72h-adm for 28-day mortality was ascertained by Cox proportional hazards model analysis.ResultsThirty-five (10.1%) patients died within 28 days after ED admission. MPV increased significantly during the first 72 hours in non-survivors (P = 0.001) and survivors (P < 0.001); however, the rate of MPV increase was significantly higher in non-survivors (P = 0.003). Nonetheless, the difference in the platelet decline rate over the first 72 hours did not differ significantly between groups (P = 0.360). In multivariate analysis, ΔMPV72h-adm was an independent predictor of 28-day mortality, after adjusting for plausible confounders (hazard ratio, 1.44; 95% confidence interval, 1.01–2.06; P = 0.044).ConclusionsAn increase in MPV during the first 72 hours of hospitalization is an independent risk factor for adverse clinical outcomes. Therefore, continuous monitoring of MPV may be useful to stratify mortality risk in patients with severe sepsis and/or septic shock.

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