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Diabetic kidney disease (DKD) is a serious microvascular complication of type 2 diabetes mellitus (T2DM). Despite the numerous genetic loci that have been associated with the disease in T2DM, the genetic architecture of DKD remains unclear until today. In contrast to SERPINE1, the contribution of SERPINB2 has not been examined in DKD. Therefore, we conducted the first genetic association study of SERPINB2 to elucidate its role in DKD. In total, the study involved 197 patients with DKD, 155 patients with T2DM without microvascular complications (diabetic kidney disease, diabetic retinopathy, and diabetic neuropathy), and 246 healthy controls. The generalized odds ratio (ORG) was calculated to estimate the risk on DKD development. The present association study regarding SERPINB2 SNPs (rs4941230, rs3819335, rs13381217, rs6140) did not reveal any significant association between SERPINB2 variants and DKD. Additional studies in other populations are necessary to further investigate the role of this gene in the progression of diabetes mellitus and development of DKD. [ABSTRACT FROM AUTHOR]

Ischemia‐reperfusion (I‐R) injury is the most common cause of acute kidney injury. In experiments involving primary human renal proximal tubular epithelial cells (RPTECs) exposed to anoxia‐reoxygenation, we explored the hypothesis that mitochondrial malate dehydrogenase‐2 (MDH‐2) inhibition redirects malate metabolism from the mitochondria to the cytoplasm, towards the malate‐pyruvate cycle and reversed malate‐aspartate shuttle. Colorimetry, fluorometry, and western blotting showed that MDH2 inhibition accelerates the malate‐pyruvate cycle enhancing cytoplasmic NADPH, thereby regenerating the potent antioxidant reduced glutathione. It also reversed the malate‐aspartate shuttle and potentially diminished mitochondrial reactive oxygen species (ROS) production by transferring electrons, in the form of NADH, from the mitochondria to the cytoplasm. The excessive ROS production induced by anoxia‐reoxygenation led to DNA damage and protein modification, triggering DNA damage and unfolded protein response, ultimately resulting in apoptosis and senescence. Additionally, ROS induced lipid peroxidation, which may contribute to the process of ferroptosis. Inhibiting MDH‐2 proved effective in mitigating ROS overproduction during anoxia‐reoxygenation, thereby rescuing RPTECs from death or senescence. Thus, targeting MDH‐2 holds promise as a pharmaceutical strategy against I‐R injury. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine, involved in the pathogenesis and progression of immunoglobulin A nephropathy (IgAN). A bi-allelic polymorphism in the promoter region, at position -308 (G/A) of the TNF-α gene (rs1800629) is associated with an increased TNF-a production. However, several previous association studies of TNF-α G-308A polymorphism and IgAN rendered contradictory findings. The objective of the present study is to shed light on these inconclusive results and clarify the role of TNF-α and any possible contribution of this factor in the development and progression of sporadic IgAN. Therefore, a meta-analysis of all available genetic association studies relating the TNF-α G-308A polymorphism to the risk for development and/or progression of IgAN was conducted. Seven studies were included in the meta-analysis. Three of them included populations of European descent (Caucasians) and four involved Asians. The generalized odds ratio (ORG) was used to estimate the risk for the development and/or progression of the disease. Overall, the meta-analysis did not detect any significant association between the G-308A variant and both the risk of developing IgAN and the risk for progression of IgAN. In conclusion, these results suggest that TNF-α does not constitute a key component in the genetic architecture of sporadic IgAN. However, further evidence deciphering the influence of TNF-α on IgAN is still needed. [ABSTRACT FROM AUTHOR]

Aims: Diabetic nephropathy (DN) has become a serious public health problem. Genetic factors are involved in the pathogenesis of DN, but the exact mode of inheritance is still unknown. Genome-wide linkage scans (GWLS) have produced inconclusive or inconsistent results. In an effort to test consistency and provide more conclusive results, we applied a heterogeneity-based genome search meta-analysis (HEGESMA) to GWLS regarding DN. Materials and Methods: We combined results from eight GWLS in the primary analysis and nine GWLS for a conditional analysis about DN for both diabetes types, as well as in each type of diabetes and ethnicity in subgroup analyses. Results: HEGESMA identified cytogenetic locations that rank highly on average in terms of linkage statistics across multiple genome scans, taking into consideration the magnitude of heterogeneity of the results between scans. Main analyses: Our meta-analysis identified 13 cytogenetic locations (bins) with statistical significance (Prank ≤ 0.05), 11 of which were significant in both weighted and unweighted analyses located on chromosomes 1q, 3q, 4p, 5q, 7q, 15q, 16p, 17q, 19q, and 22p. In addition, four novel regions (5q11.2–5q14.3, 5q23.2–5q34, 17q24.3–17q25.3, and 22q12.3–22q13.3) were identified. Seven bins on chromosomes 4p, 5q, 7q, 15q, 22p, and 22q were common between both types of diabetes and in all subgroup analyses, in addition 5q14.3–5q23.2 was significant across all analyses. Conditional analyses: meta-analysis identified nine different cytogenetic locations, among which 7p22.3–7p15.3 was significant only in type 2 diabetes mellitus conditional analysis. Ethnicity subgroup analyses identified 11 different cytogenetic locations, 5 out of which are novel findings. However, none of the chromosomal regions reached genome-wide statistical significance (Prank < 0.00042). Discussion: This meta-analysis provides evidence for linkage for nine novel cytogenetic regions that should be further investigated for genes that confer susceptibility to DN. [ABSTRACT FROM AUTHOR]

Background: The presence of an intracranial aneurysm (IA) is thought to have a genetic origin. The genetic association studies (GAS) that investigated the association between IA and elastin gene (ELN) variants have produced contradictory or inconclusive results.Materials and methods: In order to decrease the uncertainty of estimated genetic risk effects, a meta-analysis of published GAS-related variants in theELNgene (ELNINT20 1315T > C, EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A) with susceptibility to IA was conducted using a genetic model-free approach. The risk effects were estimated using the generalized odds ratio (ORG) metric.Results: The analysis showed significant association for the INT20 1315T > C variant [ORG = 0.66 (0.45–0.95)], indicating a protection effect. For the variants EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A, no statistically significant association with IAs was found.Conclusion: There is evidence that theELNvariant INT20 1315T > C is implicated in the development of IA; however, the results should be interpreted with caution since the number of published studies is limited. [ABSTRACT FROM AUTHOR]

The latest meta-analysis of genome-wide linkage studies (GWLS) identified nine cytogenetic locations suggestive of a linkage with diabetic nephropathy (DN) due to type 1 diabetes mellitus (T1DM) and seven locations due to type 2 diabetes mellitus (T2DM). In order to gain biological insight about the functional role of the genes located in these regions and to prioritize the most significant genetic loci for further research, we conducted a gene ontology analysis with an over representation test for the functional annotation of the protein coding genes. Protein analysis through evolutionary relationships (PANTHER) version 16.0 software and Cytoscape with the relevant plugins were used for the gene ontology analysis, and the overrepresentation test and STRING database were used for the construction of the protein network. The findings of the over-representation test highlight the contribution of immune related molecules like immunoglobulins, cytokines, and chemokines with regard to the most overrepresented protein classes, whereas the most enriched signaling pathways include the VEGF signaling pathway, the Cadherin pathway, the Wnt pathway, the angiogenesis pathway, the p38 MAPK pathway, and the EGF receptor signaling pathway. The common section of T1DM and T2DM results include the significant over representation of immune related molecules, and the Cadherin and Wnt signaling pathways that could constitute potential therapeutic targets for the treatment of DN, irrespective of the type of diabetes. [ABSTRACT FROM AUTHOR]