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Background and Aims Glomerular injury and proximal tubule (PT) dysfunction have intricate mechanisms in diabetic kidney disease (DKD). Pro-inflammatory cytokines are involved in the initiation and progression of DKD through mediating the inflammatory response, both at glomerular and proximal tubular level. miRNAs are able to modulate cellular and biochemical functions, thus intervening in the pathogenesis of DKD. The aim of the study, performed on patients with type 2 diabetes mellitus (DM), was to evaluate selective pro-inflammatory cytokines in relation to biomarkers of podocyte lesion and of PT dysfunction. Particular molecular pathways, such as specific miRNA profiles operating in this relation, have also been studied. Method A number of 126 patients with type 2 DM, staged by albuminuria [39 normoalbuminuric – urinary albumin/creatinine ratio UACR)300mg/g], and 23 healthy control subjects were included in a cross-sectional study. All patients were evaluated concerning biomarkers of podocyte injury (nephrin, podocalyxin, synaptopodin) and of PT dysfunction [Kidney injury molecule-1(KIM-1), N-acetyl-beta-D-glucuronidase (NAG), alpha 1- microglobulin]. Also, serum and urinary levels of specific interleukins (IL-6, IL-17), serum cystatin C, and eGFR were determined. Serum and urinary miRNAs (miRNA-21, miRNA-124, miRNA-146a, miRNA-192) were assessed by RT-PCR. Results The biomarkers of podocyte lesion and of PT dysfunction were increased, even in normoalbuminuric type 2 DM patients. Serum and urinary IL-6 and IL-17 showed increased levels in type 2 DM patients, across all groups studied. The model provided by univariable regression analysis showed that IL-6 and IL-17 correlated directly with biomarkers of podocyte injury (nephrin, podocalyxin, synaptopodin), of PT dysfunction (KIM-1, NAG, alpha 1-microglobulin), as well as with UACR. Negative correlations have been identified regarding eGFR. In multivariable regression analysis, serum IL-6 correlated directly with synaptopodin, NAG, and negatively with eGFR (p Also, important associations were found between specific interleukins and miRNAs. In univariable regression analysis, IL-6 and IL-17 correlated directly with miRNA-21 and miRNA-124, and negatively with miRNA-146a and miRNA-192. The models provided by multivariable regression analysis showed that urinary IL-6 correlated directly with urinary miRNA-21, and negatively with urinary miRNA-192 (p Conclusion In the early stages of DKD, there is an association of pro-inflammatory cytokines with specific miRNAs, and with biomarkers of podocyte injury and of PT dysfunction. IL-6 and IL-17, as well as dysregulated miRNA-21, miRNA-124, miRNA-146a, and miRNA-192 display a particular molecular pattern, in relation to complex mechanisms that can initiate and maintain the chronic inflammatory response in DKD. Routine detection of these interleukins may provide biomarkers to refine the diagnosis of early renal involvement in the course of type 2 DM, independently of albuminuria and level of renal function.

Background and Aims Interactions among multiple molecules and signalling pathways contribute to the pathogenesis and progression of diabetic kidney disease (DKD). Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aim of the study was to establish the involvement of selected lncRNAs in the epigenetic mechanisms of podocyte damage and tubular injury in DKD of type 2 diabetes mellitus (DM) patients. The molecular mechanisms of lncRNAs intervention were evaluated in relation to a particular miRNA profile. Method A total of 136 patients with type 2 DM and 25 healthy subjects were enrolled in a cross-sectional case series study and assessed concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and proximal tubule (PT) dysfunction (Kidney injury molecule-1-KIM-1, N-acetyl-D-glucosaminidase-NAG), urinary lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), myocardial infarction-associated transcript (MIAT), taurine-upregulated gene 1 (TUG1), and urinary miRNA21, 124, 93, 29a (quantified by a real-time PCR System). Results Multivariable regression analysis yielded models in which urinary lncRNA MALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93 and 29a (p Conclusion In patients with type 2 DM lncRNAs exert distinct functions in different cell types, either deleterious or protective, at both glomerular and tubular level. LncRNAs may contribute to DKD through modulating miRNAs expression and activities. This observation holds true independently of albuminuria and DKD stage.

Purpose: Searching for new biomarkers to predict the progress of coronary artery disease (CAD), we studied the evolution of lipid and inflammatory parameters, along with five mi-RNAs, in plasma of CAD patients under treatment for 1 year. Methods: Subjects were assigned to 5 groups: healthy subjects (C, 10), subjects with risk factors (RF, 10), stable angina (SA, 22), unstable angina (UA, 21) and 1 month post myocardial infarction (MI, 11) patients. Blood was collected at inclusion and after 1 year of standard treatment. We selected five miRNA (miR-92a, miR486a, miR-125a, miR-146a, miR-33a), due to their implication in lipid metabolism, cardiomyocytes and endothelial dysfunction. Lipid parameters were measured in plasma and serum, such as total cholesterol, triglycerides, phospholipids, LDL-C, HDL-C, and oxidative stress markers, such as oxidized LDL, 4-hydroxynonenal (4-HNE), 15(S)-hydroxy-eicosatetraenoic acid, 13(S)-hydroxyoctadecadienoic levels and paraoxonase-1(PON-1) activity. IL-1β, CRP, matrix metalloproteases (MMP-9, MMP-14) and soluble vascular adhesion protein (sVAP-1) were determined as inflammatory markers. The statistical correlation between biochemical and clinical parameters was performed. Results: After 1-year of treatment, our evaluation showed a significant improvement of the plasma lipid profile, decrease of the oxidative (lower plasma 4-HNE levels and increased serum PON1 activity) and inflammatory stress (lower IL-1β levels and MMP-9 activity). Interestingly, IL-1β levels were increased in sera from SA and UA patients under 60 compared to those over 60. Also, MMP-14 levels were increased in UA and decreased in MI sera from patients under 60 compared to those over 60. Levels of sVAP-1 were increased in MI (406.9±72.34) compared to UA (348.29±50.52, p