Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Diabetic nephropathy (DN) is characterized by metabolic disorder and inflammation. However, the regulatory effects that long noncoding RNAs (lncRNAs) have on the pathogenesis of DN and on the efficacy of rosiglitazone treatment have yet to be clearly defined. Herein, we performed unbiased RNA sequencing to characterize the transcriptomic profiles in db/db diabetic mouse model with or without rosiglitazone treatment that served to improve the phenotypes of DN. Moreover, RNA-seq profiling revealed that the development of DN caused an upregulation in the expression of 1176 mRNAs and a downregulation in the expression of 1010 mRNAs compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with rosiglitazone. Further, 88 upregulated and 68 downregulated lncRNAs were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with rosiglitazone. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARγ, are related to inflammatory and metabolic processes. From bioinformatics analysis, lncRNA-AI838599 emerged as a novel molecular mechanism for rosiglitazone treatment in DN through TNFα-NFκb pathway. These findings may indicate a new molecular regulatory approach for the development of DN therapeutic agents.

The PPARγ Agonist Rosiglitazone Suppresses Syngeneic Mouse SCC (Squamous Cell Carcinoma) Tumor Growth through an Immune-Mediated Mechanism

Recent evidence suggests that PPARγ agonists may promote anti-tumor immunity. We show that immunogenic PDV cutaneous squamous cell carcinoma (CSCC) tumors are rejected when injected intradermally at a low cell number (1 × 106) into immune competent syngeneic hosts, but not immune deficient mice. At higher cell numbers (5 × 106 PDV cells), progressively growing tumors were established in 14 of 15 vehicle treated mice while treatment of mice with the PPARγ agonist rosiglitazone resulted in increased tumor rejection (5 of 14 tumors), a significant decrease in PDV tumor size, and a significant decrease in tumor cell Ki67 labeling. Rosiglitazone treatment had no effect on tumor rejection, tumor volume or PDV tumor cell proliferation in immune deficient NOD.CB17-PrkdcSCID/J mice. Rosiglitazone treatment also promoted an increase in tumor infiltrating CD3+ T-cells at both early and late time points. In contrast, rosiglitazone treatment had no significant effect on myeloid cells expressing either CD11b or Gr-1 but suppressed a late accumulation of myeloid cells expressing both CD11b and Gr-1, suggesting a potential role for CD11b+Gr-1+ myeloid cells in the late anti-tumor immune response. Overall, our data provides evidence that the PPARγ agonist rosiglitazone promotes immune-mediated anti-neoplastic activity against tumors derived from this immunogenic CSCC cell line.

Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Suppresses Inflammation and Bacterial Clearance during Influenza-Bacterial Super-Infection

Influenza virus is among the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, a frequent cause of mortality. When influenza virus infects the lung, the innate immune response is activated, and interferons and inflammatory mediators are released. This “cytokine storm” is thought to play a role in influenza-induced lung pathogenesis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor super-family. PPARγ has numerous functions including enhancing lipid and glucose metabolism and cellular differentiation and suppressing inflammation. Synthetic PPARγ agonists (thiazolidinediones or glitazones) have been used clinically in the treatment of type II diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), diabetic participants taking rosiglitazone had an increased risk of mortality from influenza/pneumonia compared to those not taking the drug. We examined the effect of rosiglitazone treatment during influenza and secondary bacterial (Methicillin resistant Staphylococcus aureus) pneumonia in mice. We found decreased influenza viral burden, decreased numbers of neutrophils and macrophages in bronchoalveolar lavage, and decreased production of cytokines and chemokines in influenza infected, rosiglitazone-treated mice when compared to controls. However, rosiglitazone treatment compromised bacterial clearance during influenza-bacterial super-infection. Both human and mouse data suggest that rosiglitazone treatment worsens the outcome of influenza-associated pneumonia.

miR-876-3p regulates glucose homeostasis and insulin sensitivity by targeting adiponectin

miRNA has been known to regulate diverse cellular and molecular functions. In the earlier study, we have reported that adipocytes differentiated from human mesenchymal stem cells (hMSC) on 72-h chronic insulin (CI) treatment exhibit insulin resistance (IR). Present study has further explored above model to investigate the role of early expressed miRNAs within human adipocytes to modulate differential adipokine expression as observed during IR. Our results highlight that miR-876-3p regulate glucose homeostasis and its dysregulation leads to IR. We found that miR-876-3p level is a critical determinant of adiponectin expression by virtue of its target within adiponectin 3′UTR. Regulatory effect of miR-876-3p impacts crosstalk between adiponectin and insulin signaling. Rosiglitazone treatment in CI-induced IR adipocytes drastically reduced miR-876-3p expression and increased adiponectin level. In line with this, lentiviral-mediated inhibition of miR-876-3p expression ameliorated CI and high-fat diet (HFD)-induced IR in adipocytes differentiated from hMSC and C57BL/6 mice, respectively. Our findings thus suggest that modulating miR-876-3p expression could provide novel opportunities for therapeutic intervention of obesity-associated metabolic syndrome.