NOS3 gene intron 4 a/b polymorphism is associated with ESRD in autosomal dominant polycystic kidney disease patients

Padhi, Udit Narayan; Mulkalwar, Madhubala; Saikrishna, Lakkakula; Verma, Henu Kumar; Lakkakula, Bhaskar Vks

doi:10.1590/2175-8239-jbn-2021-0089

Cited by 4 publications

(5 citation statements)

References 35 publications

(44 reference statements)

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“…The ACP2 protein was included in a prognostic model of DKD including 35 DKD patients with good and 19 with poor prognosis [ 68 ]. On the other hand, associations in ATP5G1 , the ATP Synthase Membrane Subunit C Locus 1 represents one of the novel findings in our study [ 62 ].…”

Section: Discussionmentioning

confidence: 71%

“…NOS3 encodes the nitric oxide synthase 3, involved in endothelin pathways and the EGF/EGFR signalling pathway, whose inhibition protects against the development of DKD [ 162 ]. There is a clear link between NOS3 gene variation and ESKD [ 62 , 63 ], CKD [ 64 ] and CKD progression [ 65 ]. A recent meta-analysis of 13 studies found that two NOS3 gene polymorphisms (rs1799983, R2 = 0.189 with rs3918226 and the intron 4 VNTR a/b polymorphism) significantly increased ESKD risk in autosomal dominant polycystic kidney disease (ADPKD) patients [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…There is a clear link between NOS3 gene variation and ESKD [ 62 , 63 ], CKD [ 64 ] and CKD progression [ 65 ]. A recent meta-analysis of 13 studies found that two NOS3 gene polymorphisms (rs1799983, R2 = 0.189 with rs3918226 and the intron 4 VNTR a/b polymorphism) significantly increased ESKD risk in autosomal dominant polycystic kidney disease (ADPKD) patients [ 62 ]. The rs1799983 variant has also showed a role in development of CKD in a recent meta-analysis [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

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Genetic variants affecting mitochondrial function provide further insights for kidney disease

Cañadas-Garre,

Baños-Jaime,

Maqueda

et al. 2024

BMC Genomics

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Background Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. Methods We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. Results Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. Conclusions We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetic variants affecting mitochondrial function provide further insights for kidney disease

Cañadas-Garre,

Baños-Jaime,

Maqueda

et al. 2024

BMC Genomics

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“…It should be noted that the presence of the 4a allele may be related to kidney dysfunction and other pathological conditions. Thus, there are data on the association of the rs61722009 variant of the NOS3 gene with the progression of nephropathy in patients with diabetes and Fabry disease, an increased risk of end-stage renal failure in patients with autosomal polycystic kidney disease [ 15 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

NOS3 (rs61722009) gene variants testing in prediction of COVID-19 pneumonia severity

et al. 2023

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“…eNOS genes have been implicated in renal hemodynamics as potent regulators of vascular tone. 46 In this study, to understand the multiple, overlapping factors that affect renal hemodynamics, ultrasonography was used to provide a real-time and dynamic assessment of renal cortex microvascular perfusion and hemodynamic characteristics. 47 Several studies have shown that progressive exacerbation of DN is accompanied by a decrease in renal artery blood flow velocity and an increase in renal artery resistance.…”

Section: Discussionmentioning

confidence: 99%

TNF-α and IL-1β Promote Renal Podocyte Injury in T2DM Rats by Decreasing Glomerular VEGF/eNOS Expression Levels and Altering Hemodynamic Parameters

Wang¹,

Feng²,

Zhang³

et al. 2022

JIR

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Purpose Diabetic nephropathy (DN) is a serious microvascular complication in those with type 2 diabetes mellitus (T2DM). Evidence confirms that serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the T2DM stage are proposed as prognostic markers for DN development, but it is unclear how they affect renal podocyte-associated nephrin and WT-1 expression. In the presence of podocyte injury, glomerular vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and hemodynamic parameters are dysregulated. The current research aimed to clarify the relationship of TNF-α and IL-1β with podocyte injury by altering VEGF/eNOS expression and hemodynamic parameters. Methods A high-fat diet/streptozotocin-induced DN rat model was established. Serum TNF-α and IL-1β levels were tracked in the pre-T2DM, T2DM and DN stages. In the DN stage, the mRNA and protein expression levels of renal TNF-α, IL-1β, VEGF, eNOS, nephrin and WT-1 were studied. Renal hemodynamic parameters, including peak systolic velocity, end-diastolic flow velocity and mean velocity were measured with a color Doppler ultrasound technique. Results Compared to those in the normal control (CTL) group, serum TNF-α and IL-1β levels increased significantly in the pre-T2DM stage (obesity, insulin resistance and hyperlipidemia), T2DM stage (hyperglycemia) and DN stage (abnormal renal functions) (all: P < 0.05) in the DN group. Serum TNF-α and IL-1β levels in the T2DM stage were significantly higher than those in the pre-T2DM stage (two: P < 0.05). Compared to the CTL group, renal nephrin, WT-1, TNF-α, IL-1β, eNOS and VEGF expression and hemodynamic parameters in the DN stage all showed significant differences separately (all: P < 0.05). Conclusion Increased serum and renal TNF-α and IL-1β levels played important roles in reducing renal nephrin and WT-1 expression levels, which may be related to the fact that the former affected renal VEGF/eNOS expression and blood flow parameters in the DN rats.

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NOS3 gene intron 4 a/b polymorphism is associated with ESRD in autosomal dominant polycystic kidney disease patients

Cited by 4 publications

References 35 publications

Genetic variants affecting mitochondrial function provide further insights for kidney disease

Genetic variants affecting mitochondrial function provide further insights for kidney disease

NOS3 (rs61722009) gene variants testing in prediction of COVID-19 pneumonia severity

TNF-α and IL-1β Promote Renal Podocyte Injury in T2DM Rats by Decreasing Glomerular VEGF/eNOS Expression Levels and Altering Hemodynamic Parameters

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