Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia

Padhy, Gayatri; Gangwar, Anamika; Sharma, Manish; Himashree, Gidugu; Singh, Krishan; Bhaumik, Gopinath; Bhargava, Kalpana; Sethy, Niroj Kumar

doi:10.1016/j.niox.2016.02.009

Cited by 14 publications

(11 citation statements)

References 45 publications

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“…We found increased methylation of SOD3 , which we expect to be associated with decreased expression of its protein, since the region we assessed is upstream of the SOD3 promoter. This is in line with previous research demonstrating decreased levels of SOD3 among high-altitude natives of India, the Ladakhi, compared with acclimatized lowlanders ( Padhy et al. 2016 ).…”

Section: Discussionsupporting

confidence: 93%

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes

Childebayeva

Goodrich

León‐Velarde³

et al. 2020

Genome Biology and Evolution

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High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled Nitric Oxide (FeNO) also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

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Section: Discussionsupporting

confidence: 93%

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes

Childebayeva

Goodrich

León‐Velarde³

et al. 2020

Genome Biology and Evolution

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“…Plasma kallikrein (encoded by the gene kallikrein B1[KLKB1]) has kininogenase activity through high-molecular-weight kininogen (HMWK) and it circulates in the blood as an inactive pre-kallikrein, bound to its cofactor HMWK. Cleavage of the kallikrein-HMWK complex leads to the release of the vasoactive peptide bradykinin, thus affecting vasodilation and inflammation, but, more importantly, it leads to increased NO release and bioavailability [2] and fibrin degradation [3], functions that may potentially be vasoprotective. Although it is widely accepted that the plasma KKS, as part of the contact-activated cascade, is locally assembled and profoundly silenced by various plasma inhibitors, accumulating evidence indicates that plasma KKS is activated by contact with an activated endothelial surface [4][5][6][7].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes

et al. 2020

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Aims/hypothesis Plasma kallikrein is the central mediator of the plasma kallikrein-kinin system, which is involved both in vascular control and thrombin formation cascades. The plasma kallikrein-kinin system has also been considered protective in pathological conditions, but the impact of plasma kallikreins on diabetic nephropathy remains unknown. The objective of this cross-sectional study was to explore the association of plasma kallikrein with diabetic nephropathy. Methods We measured plasma kallikrein activity in 295 individuals with type 1 diabetes at various stages of diabetic nephropathy, and we tested the genetic association between the plasma kallikrein-kinin system and kidney function in 4400 individuals with type 1 diabetes. Results Plasma kallikrein activity was associated with diabetes duration (p < 0.001) and eGFR (p < 0.001), and plasma kallikrein activity was lower with more advanced diabetic nephropathy, being lowest in individuals on dialysis. The minor alleles of the KNG1 rs5030062 and rs710446 variants, which have previously been associated with increased plasma pre-kallikrein and/or factor XI (FXI) protein levels, were associated with higher eGFR (rs5030062 β = 0.03, p = 0.01; rs710446 β = 0.03, p = 0.005) in the FinnDiane cohort of 4400 individuals with type 1 diabetes. Conclusions/interpretation Plasma kallikrein activity and genetic variants known to increase the plasma kallikrein level are associated with higher eGFR in individuals with type 1 diabetes, suggesting that plasma kallikrein might have a protective effect in diabetic nephropathy.

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“…Bradykinin, B1R, and B2R belong to the Kallikrein-kinin system (KKS). KKS is widely distributed in the central nervous system and plays an important regulatory role in various pathological processes and physiological functions, such as cerebrovascular disease, central nervous system degeneration, inflammation process, and tumor progression in the brain, , as well as the adjustment of blood pressure, the stabilization of the body environment, and the regeneration of blood vessels. , KKS also plays an important role in improving kidney and brain ischemia-reperfusion injury. , …”

Section: Introductionmentioning

confidence: 99%

“…1,9 KKS also plays an important role in improving kidney and brain ischemia-reperfusion injury. 10,11 T h i s c o n t e n t i s The function of each component of KKS has been investigated. Studies have reported that B1R and B2R are involved in a series of physiological and pathological processes like apoptosis, blood-brain barrier damage, neurotoxicity, inflammation, and tissue edema.…”

Section: ■ Introductionmentioning

confidence: 99%

Bradykinin Activates the Bradykinin B2 Receptor to Ameliorate Neuronal Injury in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury

Yang

Yao

et al. 2021

ACS Chem. Neurosci.

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Bradykinin and bradykinin B2 receptors (B2R) play important roles in both the peripheral and central nervous systems. The aim of this study was to explore the changes of bradykinin and B2R in spinal cord ischemic injury (SCII) and whether bradykinin treatment would improve the neurologic function of SCII rats. The rats were divided into the sham group, the SCII group, and three doses of bradykinin (50, 100, 150 μg/kg) groups. The neurologic function was assessed by the Basso, Beattie, and Bresnahan (BBB) score at −1, 1, 3, 5, and 7 days postsurgery. Bradykinin concentration in serum and IL-6, TNF-α, and MCP-1 levels in the spinal cord were detected by ELISA. The mRNA expressions of B2R, IL-6, TNF-α, MCP-1, COX-2, and iNOS in the spinal cord were determined by RT-PCR. The protein expressions of B2R, COX-2, iNOS, p65, and p-p65 were detected by Western blot. Immunohistochemical staining was used to examine B2R expression in the L4−6 segments of the spinal cord. Bradykinin levels in serum and B2R expression in the spinal cord were downregulated in SCII rats. Bradykinin treatment significantly improved the hind limb motor function of SCII rats and increased B2R expression, inhibiting COX-2, iNOS, and p-p65 expression in the spinal cord of SCII rats together with a decrease of the inflammatory mediators of IL-6, TNF-α, and MCP-1 levels. Bradykinin administration activated B2R in the spinal cord of SCII rats, which may improve hind limb locomotor recovery by regulating the NF-κB signaling pathway to inhibit the inflammatory response. These findings may provide a theoretical basis for the clinical application of bradykinin in SCII.

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Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia

Cited by 14 publications

References 45 publications

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes

Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes

Bradykinin Activates the Bradykinin B2 Receptor to Ameliorate Neuronal Injury in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury

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