Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Therefore, understanding the molecular regulatory mechanisms underlying the pathogenesis of DKD is imperative. In this study, we aimed to explore the molecular mechanisms of tubule region endothelial dysfunction in early DKD. Early-stage DKD model was established in 16-week-old female db/db mice for 16 weeks. Body weight, glucose level, and urine albumin-to-creatinine ratio (UACR) were measured. Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed to evaluate pathological lesions. RNA sequencing data of the kidneys and integrated publicly available single-cell and spatial transcriptome datasets were used to investigate the mechanism of endothelial dysfunction. There was a significant increase in body weight (p = 0.001), glucose levels (p=0.0008), and UACR (p=0.006) in db/db mice compared with db/m mice. H&E and PAS staining showed that vacuolar lesions and protein casts of tubules were the major histopathological changes observed in early-stage DKD mice. The apoptotic pathway in endothelial cells was notably activated in DKD, and Thbs1 was identified as the central gene involved in this apoptotic process. Deconvolution of the cell composition in the RNA sequencing data showed a decrease in the proportion of endothelial cells in the DKD mice. Further analysis of the activity and regulatory network of transcription factors showed that Creb1 was activated in both mouse and human early-stage DKD, suggesting that Creb1 activation may be involved in early kidney injury. The endothelial cell apoptotic pathway is activated in DKD, and the proportion of endothelial cells was reduced in the DKD mice, which is significantly associated with Thbs1. Keywords: Diabetic kidney disease, Endothelial dysfunction, RNA sequencing,Thbs1, Creb1.

• MeSH
• cévní endotel * patologie   metabolismus   patofyziologie   MeSH
• diabetické nefropatie * patologie   metabolismus   genetika   patofyziologie   MeSH
• endoteliální buňky * patologie   metabolismus   MeSH
• ledvinové kanálky * patologie   metabolismus   patofyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• progrese nemoci MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.

• Klíčová slova
• Diabetes mellitus, Diabetic kidney disease, Genetic predisposition, Genetic risk score, Single nucleotide polymorphism,
• MeSH
• celogenomová asociační studie MeSH
• chronická renální insuficience * genetika   patologie   MeSH
• diabetes mellitus 2. typu * genetika   komplikace   MeSH
• diabetické nefropatie * genetika   MeSH
• genetická predispozice k nemoci * MeSH
• genetické rizikové skóre MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• progrese nemoci * MeSH
• rizikové faktory MeSH
• senioři MeSH
• sfingosin-N-acyltransferasa genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• sfingosin-N-acyltransferasa MeSH

BACKGROUND: Genome-wide association studies have resulted in the identification of the FTO gene as an important genetic determinant of diabetes mellitus. The aim of this study was to confirm the role of this gene in the development of DM in the Czech-Slavonic population and to analyse whether this gene is associated with common DM complications. METHODS: Two groups of patients (814 with T1DM and 848 with T2DM) and a group of healthy controls (2339 individuals) - both of Czech origin - were genotyped for the FTO rs17817449 SNP. ANOVA and logistic regression were used for the statistical evaluations. RESULTS: The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P<0.0005) but not in T1DM patients (19.3% vs. 16.7%, P=0.20) than in controls. The increased risk of development of diabetic nephropathy was observed both for T1DM patients (GG vs. TT homozygotes, P<0.01) and T2DM patients (G carriers vs. TT homozygotes, P<0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P<0.01) in the T2DM patients only. No association between FTO genotype and development of retinopathy was detected. All presented values are after adjustment for age, sex, BMI and duration of diabetes. CONCLUSIONS: We confirm the association between the FTO rs17817449 SNP and susceptibility to T2DM in the Czech-Slavonic population. The same variant is associated with a spectrum of chronic complications in both types of diabetes.

• Klíčová slova
• BMI, Chronic complications, Diabetes mellitus, FTO, SNP,
• MeSH
• diabetes mellitus 1. typu komplikace   genetika   MeSH
• diabetes mellitus 2. typu komplikace   genetika   MeSH
• diabetická retinopatie genetika   MeSH
• diabetické nefropatie genetika   MeSH
• diabetické neuropatie genetika   MeSH
• dospělí MeSH
• gen pro FTO genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• FTO protein, human MeSH Prohlížeč
• gen pro FTO MeSH

The number of type 2 diabetic patients is increasing world-wide and a prediction of prevalence of chronic kidney disease up to 2025 in European diabetic population is alarming. Albuminuria and estimated glomerular filtration rate are cardinal biochemical parameters in diagnostics of diabetic nephropathy. Following diagnostic methods are also used: renal ultrasonography, ophthalmoscopy and in not clarified cases renal biopsy. Long-term optimal glycemic control, efficient antihypertensive treatment by angiotensin converting enzyme inhibitor, or angiotensin receptor blocker and recommended protein intake is a cornerstone of therapy. The research is presently focused on new pathophysiological mechanisms, as analysis of genome, microRNA, kidney injury biomarkers and proteomes.Key words: chronic kidney disease - type 2 diabetes mellitus.

• MeSH
• albuminurie diagnóza   farmakoterapie   etiologie   genetika   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• antihypertenziva terapeutické užití   MeSH
• biopsie MeSH
• chronická renální insuficience diagnóza   farmakoterapie   etiologie   genetika   MeSH
• diabetes mellitus 2. typu komplikace   diagnóza   farmakoterapie   MeSH
• diabetické nefropatie diagnóza   farmakoterapie   etiologie   genetika   MeSH
• genomika MeSH
• hodnoty glomerulární filtrace MeSH
• inhibitory ACE terapeutické užití   MeSH
• ledviny diagnostické zobrazování   patologie   MeSH
• lidé MeSH
• mikro RNA MeSH
• oftalmoskopie MeSH
• proteomika MeSH
• ultrasonografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté receptorů pro angiotenzin MeSH
• antihypertenziva MeSH
• inhibitory ACE MeSH
• mikro RNA MeSH

BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Several lines of evidence implicate the endothelin (ET) system in the pathophysiology of DN. The aim of the present study was to analyze if genetic polymorphisms of the ET-1 (EDN1) gene affect susceptibility to DN in Caucasians with T2DM. MATERIALS AND METHODS: The study population consisted of 651 Caucasian subjects with T2DM of more than 10 years' duration: 276 patients with DN (cases) and 375 patients without evidence of DN (controls). Polymorphisms in ET-1 (EDN1) gene, rs5370, rs1476046, and rs3087459, were studied. RESULTS: Genotype distributions of the studied polymorphisms showed no significant difference between cases and controls. CONCLUSIONS: We provide evidence that the rs5370, rs1476046, and rs3087459 polymorphisms of EDN1 gene are not risk factors for DN in Caucasians with T2DM.

• Klíčová slova
• diabetic nephropathy, endothelin-1 gene polymorphisms, type 2 diabetes mellitus,
• MeSH
• běloši genetika   MeSH
• diabetes mellitus 2. typu etnologie   genetika   patofyziologie   MeSH
• diabetické nefropatie etnologie   genetika   patofyziologie   MeSH
• dospělí MeSH
• endotelin-1 genetika   MeSH
• genetická predispozice k nemoci epidemiologie   MeSH
• hodnocení rizik MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• průřezové studie MeSH
• referenční hodnoty MeSH
• retrospektivní studie MeSH
• senzitivita a specificita MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endotelin-1 MeSH

Hyperglycemia, a major metabolic disturbance present in diabetes, promotes oxidative stress. Activation of antioxidant defense is an important mechanism to prevent cell damage. Levels of heavy metals and their binding proteins can contribute to oxidative stress. Antiradical capacity and levels of metallothionein (MT), metals (zinc and copper), and selected antioxidants (bilirubin, cysteine, and glutathione) were determined in 70 type 2 diabetes mellitus (T2DM) subjects and 80 healthy subjects of Caucasian origin. Single nucleotide polymorphism (rs28366003) in MT gene was detected. Antiradical capacity, conjugated bilirubin, and copper were significantly increased in diabetics, whereas MT and glutathione were decreased. Genotype AA of rs28366003 was associated with higher zinc levels in the diabetic group. The studied parameters were not influenced by renal function. This is the first study comprehensively investigating differences in MT and metals relevant to oxidative stress in T2DM. Ascertained differences indicate increased oxidative stress in T2DM accompanied by abnormalities in non-enzymatic antioxidant defense systems.

• Klíčová slova
• diabetes, diabetic kidney disease, heavy metals, metallothionein, oxidative stress,
• MeSH
• biologické markery krev   MeSH
• chronická renální insuficience krev   genetika   patofyziologie   MeSH
• diabetes mellitus 2. typu komplikace   MeSH
• diabetické nefropatie krev   genetika   patofyziologie   MeSH
• genetické asociační studie MeSH
• jednonukleotidový polymorfismus MeSH
• ledviny patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď krev   MeSH
• metalothionein krev   genetika   MeSH
• oxidační stres * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• zinek krev   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• biologické markery MeSH
• měď MeSH
• metalothionein MeSH
• MT2A protein, human MeSH Prohlížeč
• zinek MeSH

BACKGROUND/AIMS: Calcium-Sensing Receptor (CaSR) significantly affects calcium-phosphate metabolism in kidneys, and it is implicated in the pathogenesis of diabetes mellitus (DM) due to its expression in pancreatic β-cells. The role of CaSR as one of the players in pathogenesis of chronic kidney disease (CKD) has been speculated. METHODS: 158 Type 2 diabetic patients divided into three groups according to occurrence and type of kidney complications, 66 nondiabetic patients CKD, and 93 healthy subjects were enrolled into the study to analyze the role of two CaSR polymorphisms (in the codon 990 and in the intron 4) in ethiopathogenesis of DM and CKD. The Type 2 diabetic groups consisted of 48 patients without any kidney abnormalities, 58 patients with diabetic nephropathy (DN), and 52 patients with nondiabetic renal disease (NDRD). The distribution of genotype and allele frequencies was studied using PCR with the TaqMan Discrimination Assay or followed by the Restriction Fragment Length Polymorphism method, respectively. RESULTS: We have found that the intron 4 polymorphism is a risk factor for the development of DM and CKD, except DN, while the codon 990 does not show any disease association. CONCLUSION: We conclude that CaSR is a general factor in pancreas and kidney pathologies.

• MeSH
• chronická nemoc MeSH
• diabetes mellitus 2. typu diagnóza   genetika   MeSH
• diabetické nefropatie diagnóza   genetika   MeSH
• dospělí MeSH
• introny genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• komplikace diabetu diagnóza   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci ledvin diagnóza   genetika   MeSH
• receptory "calcium-sensing" genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CASR protein, human MeSH Prohlížeč
• receptory "calcium-sensing" MeSH

BACKGROUND: Anemia is a major complication of end-stage renal disease. Hemodialysis itself is regarded as a stimulus activating inflammation. Pro-inflammatory cytokines are able to suppress erythropoiesis. In this pilot study, we analyzed the changes in methylation status of promoters of immune response genes in cell-free DNA to detect the differences between diabetic subjects (n = 18) with different therapeutic doses of recombinant erythropoietin. METHODS: The extent of promoter methylation of 24 genes in plasma cell-free DNA was examined before and after hemodialysis using EpiTect Methyl qPCR Array Inflammatory Response and Autoimmunity (Qiagen). RESULTS: The patients with higher methylation status of gene sequences IL13RA1, IL15, EDG3 and INHA in interdialytic interval were significantly overrepresented in the group with none or mild anemia therapy. CONCLUSION: The results are in agreement with the fact that IL13 and IL15 are known inhibitors of erythropoiesis and with considered immunomodulatory role of cell-free DNA.

• MeSH
• anemie farmakoterapie   etiologie   MeSH
• cytokiny genetika   MeSH
• diabetické nefropatie komplikace   genetika   imunologie   terapie   MeSH
• dialýza ledvin škodlivé účinky   MeSH
• erythropoetin terapeutické užití   MeSH
• imunita genetika   MeSH
• lidé MeSH
• metylace DNA * MeSH
• promotorové oblasti (genetika) * MeSH
• shluková analýza MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• erythropoetin MeSH

BACKGROUND/AIMS: We have previously associated SNP 894G>T in the NOS3 gene with diabetic nephropathy (DN) using multi-locus analysis. Variant 894G>T has been widely studied as a DN susceptibility factor with contradictory results. In the present study we genotyped 894G>T in the cohort of prospectively followed type 2 diabetics with the aim to investigate its possible role in the progression of DN and development of morbidity and mortality associated with diabetes. METHODS: 311 subjects with defined stage of DN were enrolled in the study and followed up for a median of 38 months. We considered three end-points: progression of DN, major cardiovascular event and all-cause mortality. RESULTS: Considering baseline GFR, age at enrolment and diabetes duration as confounders, Cox regression analysis identified 894GT genotype as a risk factor for DN progression (HR = 1.843 [95% CI 1.088 - 3.119], P = 0.023) and 894TT genotype as a risk factor for major cardiovascular event (HR = 2.515 [95% CI 1.060 - 5.965], P = 0.036). CONCLUSION: We ascertained the significant effect of the NOS3 894G>T variant on DN progression and occurrence of major cardiovascular event in T2DM subjects. Based on these results NOS3 can be considered a modifier gene for DN.

• MeSH
• diabetes mellitus 2. typu enzymologie   genetika   MeSH
• diabetická kardiomyopatie enzymologie   epidemiologie   genetika   MeSH
• diabetické nefropatie enzymologie   epidemiologie   genetika   MeSH
• hodnoty glomerulární filtrace MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• polymorfismus genetický genetika   MeSH
• progrese nemoci MeSH
• prospektivní studie MeSH
• senioři MeSH
• synthasa oxidu dusnatého, typ III genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• NOS3 protein, human MeSH Prohlížeč
• synthasa oxidu dusnatého, typ III MeSH

BACKGROUND/AIMS: Complex interplay of genetic and (patho)physiological factors influence availability of nitric oxide during the development and progression of diabetic complications. We assessed predictive value of commonly studied methylated asymmetric and symmetric dimethylarginines (ADMA and SDMA) and selected single nucleotide polymorphisms (SNPs) in dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes for the progression of diabetic nephropathy (DN). METHODS: A total of 341 type 1 and type 2 diabetes patients with variable degree of kidney disease were included at baseline. Plasma levels of ADMA, SDMA and L-arginine were measured and six tagging SNPs in DDAH1 and 2 were determined. Progression of DN was defined as a transition from any given stage to a more advanced stage of albuminuria. Competing risk analysis was applied. RESULTS: Plasma levels of ADMA and SDMA significantly correlated with GFR. No significant genotype-phenotype relationship was ascertained for ADMA and DDAH variants, but SNP rs805304 exhibited marginally significant association with DN. ADMA, SDMA and L-arginine/ADMA ratio standardised to GFR were identified as significant predictors of DN progression but not GFR decline using multivariate competing risk analysis. CONCLUSIONS: In our study we confirmed potentially significant role of ADMA and SDMA for the assessment of risk of DN progression in European diabetic population.

• MeSH
• amidohydrolasy genetika   MeSH
• arginin analogy a deriváty   krev   genetika   MeSH
• diabetes mellitus 1. typu komplikace   MeSH
• diabetes mellitus 2. typu komplikace   MeSH
• diabetické nefropatie * krev   etiologie   genetika   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace MeSH
• multivariační analýza MeSH
• následné studie MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• progrese nemoci * MeSH
• průřezové studie MeSH
• reprodukovatelnost výsledků MeSH
• rizikové faktory MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• amidohydrolasy MeSH
• arginin MeSH
• dimethylargininase MeSH Prohlížeč
• N,N-dimethylarginine MeSH Prohlížeč
• symmetric dimethylarginine MeSH Prohlížeč