BackgroundThere is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. Urinary excretion of nephrin and vascular endothelial growth factor may increase even in the normoalbuminuria stage. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor.Materials and MethodsTwo groups of consecutive Type 2 diabetes mellitus outpatients (38 normo-, 32 microalbuminuric) and 21 healthy subjects were enrolled in a cross-sectional study and evaluated concerning the relation of proximal tubule dysfunction with the podocyte biomarkers excretion, assessed by ELISA methods. The impact of advanced glycation end-products on this relation was also queried.ResultsUrinary alpha1-microglobulin and kidney injury molecule-1 correlated with urinary albumin:creatinine ratio (R2 = 0.269; p<0.001; R2 = 0.125; p<0.001), nephrinuria (R2 = 0.529; p<0.001; R2 = 0.203; p<0.001), urinary vascular endothelial growth factor (R2 = 0.709; p<0.001; R2 = 0.360; p<0.001), urinary advanced glycation end-products (R2 = 0.578; p<0.001; R2 = 0.405; p<0.001), serum cystatin C (R2 = 0.130; p<0.001; R2 = 0.128; p<0.001), and glomerular filtration rate (R2 = 0.167; p<0.001; R2 = 0.166; p<0.001); nephrinuria and urinary vascular endothelial growth factor correlated with urinary albumin:creatinine ratio (R2 = 0.498; p<0.001; R2 = 0.227; p<0.001), urinary advanced glycation end-products (R2 = 0.251; p<0.001; R2 = 0.308; p<0.001), serum cystatin C (R2 = 0.157; p<0.001; R2 = 0.226; p<0.001), and glomerular filtration rate (R2 = 0.087; p = 0.007; R2 = 0.218; p<0.001).ConclusionsIn Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage. This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention. Podocyte damage and proximal tubule dysfunction biomarkers could be validated as a practical approach to the diagnosis of early diabetic nephropathy by further studies on larger cohorts.

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AimThe study assessed mRNA expression of podocyte-associated molecules in urinary sediments of patients with type 2 diabetes mellitus (DM) in relation to urinary podocytes, biomarkers of podocyte injury and of proximal tubule (PT) dysfunction.MethodsA total of 76 patients with type 2 DM and 20 healthy subjects were enrolled in a cross-sectional study, and assessed concerning urinary podocytes, urinary mRNA of podocyte-associated genes, urinary biomarkers of podocyte damage and of PT dysfunction.ResultsWe found significant differences between urinary mRNA of podocyte-associated molecules in relation with albuminuria stage. In multivariable regression analysis, urinary mRNA of nephrin, podocin, alpha-actinin-4, CD2-associated protein, glomerular epithelial protein 1 (GLEPP1), ADAM 10, and NFκB correlated directly with urinary podocytes, albuminuria, urinary alpha1-microglobulin, urinary kidney-injury molecule-1, nephrinuria, urinary vascular endothelial growth factor, urinary advanced glycation end-products (AGE), and indirectly with eGFR (p < 0.0001, R2 = 0.808; p < 0.0001, R2 = 0.825; p < 0.0001, R2 = 0.805; p < 0.0001, R2 = 0.663; p < 0.0001, R2 = 0.726; p < 0.0001, R2 = 0.720; p < 0.0001, R2 = 0.724).ConclusionsIn patients with type 2 DM there is an association between urinary mRNA of podocyte-associated molecules, biomarkers of podocyte damage, and of PT dysfunction. GLEPP1, ADAM10, and NFκB may be considered additional candidate molecules indicative of early diabetic nephropathy. AGE could be involved in this association.

Introduction: The aim of our study was to clarify the hypothesis that proximal tubule (PT) dysfunction may be responsible for early diabetic nephropathy (DN), independently of preceding glomerular endothelial dysfunction. The pattern of endothelial dysfunction and its potential variability was evaluated in two vascular beds, the kidney and the brain. Methods: A total of 68 normoalbuminuric type 2 diabetes mellitus (DM) patients were enrolled in a cross-sectional study and the following parameters were assessed: urinary albumin:creatinine ratio (UACR), urinary α₁-microglobulin, urinary β₂-microglobulin, plasma asymmetric dimethyl-arginine (ADMA), serum creatinine, glomerular filtration rate (GFR), C-reactive protein (CRP), fibrinogen, HbA_1c; pulsatility and resistance indices in the internal carotid artery and middle cerebral artery and intima-media thickness (IMT) in the common carotid artery; cerebrovascular reactivity was evaluated through the breath-holding test. Results: Plasma ADMA was increased in 12 patients (17.5%), urinary α₁-microglobulin in 19 patients (27.9%) and urinary β₂-microglobulin in 16 patients (23.5%). Cerebral hemodynamic indices correlated with plasma ADMA, CRP, fibrinogen, duration of DM, HbA_1c and GFR. ADMA correlated with fibrinogen, CRP, HbA_1c, duration of DM and GFR. There were no correlations between ADMA and UACR, and urinary α₁-/β₂-microglobulin. Also, no correlations were found between urinary α₁-/β₂-microglobulin and UACR, HbA_1c, duration of DM and GFR. Conclusion: The increase in urinary α₁-/β₂-microglobulin precedes the stage of albuminuria. It may be assumed that early DN is related to PT dysfunction. Endothelial dysfunction plays a pivotal role in the brain vasculature, while its involvement in the development of early DN is not conditional on the occurrence of albuminuria.

Aims: Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aims of the study were 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 in relation to a particular miRNAs profile. Methods: A total of 136 patients with type 2 DM and 25 healthy subjects were assessed in a cross-sectional study concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and of 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), urinary miRNA21, 124, 93, 29a. Results: Multivariable regression analysis showed that urinary lncMALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93, 29a (p<0.0001; R 2 =0.727); urinary lncNEAT1 correlated directly with synaptopodin, KIM-1, NAG, miRNA21, 124, and negatively with eGFR, miRNA93, 29a (p<0.0001; R 2 =0.702); urinary lncMIAT correlated directly with miRNA93 and 29a, eGFR (p<0.0001; R 2 =0.671) and negatively with synaptopodin, KIM-1, NAG, UACR, miRNA21, 124 (p<0.0001; R 2 =0.654); urinary lncTUG1 correlated directly with eGFR, miRNA93, 29a, and negatively with synaptopodin, podocalyxin, NAG, miRNA21, 124 (p<0.0001; R 2 =0.748). Conclusions: In patients with type 2 DM lncRNAs exert either deleterious or protective functions within glomeruli and PT. LncRNAs may contribute to DKD through modulating miRNAs expression and activities. This observation holds true independently of albuminuria and DKD stage.