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Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka.

ABSTRACT: Objective. To infer the influence of internal and external oxidative stress in chronic kidney disease patients of unknown etiology (CKDu) in Sri Lanka, by analyzing expression of genes related directly or indirectly to oxidative stress: glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase mu 1 (GSTM1), glucose-6-phosphate dehydrogenase (G6PD), fibroblast growth factor-23 (FGF23), and NLR family pyrin domain containing 3 (NLRP3). Methods. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was carried out for the selected populations: CKDu patients (n = 43), chronic kidney disease patients (CKD; n = 14), healthy individuals from a CKDu endemic area (GHI; n = 9), and nonendemic area (KHI; n = 16). Fold changes were quantified relative to KHI. Results. GCLC had greater than threefold upregulation in all three study groups, with a maximum of 7.27-fold upregulation in GHI (p = 0.000). GSTM1 was not expressed in 25.6% of CKDu and 42.9% of CKD patients, but CKDu patients expressing GSTM1 showed upregulation of 2.60-fold (p < 0.05). Upregulation of FGF23 and NLRP3 genes in CKD and CKDu was observed (p < 0.01), with greater fold changes in CKD. Conclusion. Results suggest higher influence of external sources of oxidative stress in CKDu, possibly owing to environmental conditions.

SUBMITTER: Sayanthooran S

PROVIDER: S-EPMC5128695 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka.

Sayanthooran Saravanabavan S Magana-Arachchi Dhammika N DN Gunerathne Lishanthe L Abeysekera Tilak D J TD Sooriyapathirana Suneth S SS

BioMed research international 20161116

<i>Objective.</i> To infer the influence of internal and external oxidative stress in chronic kidney disease patients of unknown etiology (CKDu) in Sri Lanka, by analyzing expression of genes related directly or indirectly to oxidative stress: glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase mu 1 (GSTM1), glucose-6-phosphate dehydrogenase (G6PD), fibroblast growth factor-23 (FGF23), and NLR family pyrin domain containing 3 (NLRP3). <i>Methods.</i> Reverse transcripti ...[more]

PMID: 27975059

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Project description:BackgroundGenus Anopheles is a major mosquito group of interest in Sri Lanka as it includes vectors of malaria and its members exist as species complexes. Taxonomy of the group is mainly based on morphological features, which are not conclusive and can be easily erased while handling the specimens. A combined effort, using morphology and DNA barcoding (using the markers cytochrome c oxidase subunit I (COI) gene and internal transcribed spacer 2 (ITS2) region, was made during the present study to recognize anophelines collected from eight districts of Sri Lanka for the first time.MethodsCytochrome c oxidase subunit I and ITS2 regions of morphologically identified anopheline mosquitoes from Sri Lanka were sequenced. These sequences together with GenBank sequences were used in phylogenetic tree construction and molecular characterization of mosquitoes.ResultsAccording to morphological identification, the field-collected adult mosquitoes belonged to 15 species, i.e., Anopheles aconitus, Anopheles annularis, Anopheles barbirostris, Anopheles culicifacies, Anopheles jamesii, Anopheles karwari, Anopheles maculatus, Anopheles nigerrimus, Anopheles pallidus, Anopheles peditaeniatus, Anopheles pseudojamesi, Anopheles subpictus, Anopheles tessellatus, Anopheles vagus, and Anopheles varuna. However, analysis of 123 COI sequences (445 bp) (16 clades supported by strong bootstrap value in the neighbour joining tree and inter-specific distances of >3%) showed that there are 16 distinct species. Identity of the morphologically identified species, except An. subpictus, was comparable with the DNA barcoding results. COI sequence analysis showed that morphologically identified An. subpictus is composed of two genetic entities: An. subpictus species A and species B (inter-specific K2P distance 0.128). All the four haplotypes of An. culicifacies discovered during the present study belonged to a single species. ITS2 sequences (542 bp) were obtained for all the species except for An. barbirostris, An. subpictus species B, An. tessellatus, and An. varuna. Each of these sequences was represented by a single species-specific haplotype.ConclusionsThe present study reflects the importance and feasibility of COI and ITS2 genetic markers in identifying anophelines and their sibling species, and the significance of integrated systematic approach in mosquito taxonomy. Wide distribution of malaria vectors in the country perhaps indicates the potential for re-emergence of malaria in the country.

Project description:During the last two decades, Sri Lanka, located close to the equator, has experienced an escalating incidence of chronic kidney disease (CKD) of unknown aetiology (CKDue) in dry zonal areas. Similar incidences of unusual CKDs have been reported in the dry zonal, agricultural areas of several other equatorial countries. In Sri Lanka, the incidence of CKDue is highest in the North Central Province (NCP), where approximately 45 % of the country's paddy fields are located. However, in recent years, the disease has spread into areas adjacent to as well as distant from the NCP. The cause of CKD in Sri Lanka is unknown, and may likely due to interactions of different potential agents; thus, CKD is of multi-factorial origin (CKD-mfo). These factors include, the negative effects from overuse of agrochemicals. Nevertheless, the potential interactions and synergism between probable agents have not been studied. This systematic review discusses the proposed hypotheses and causes of CKD-mfo in Sri Lanka, and ways to decrease the incidence of this disease and to eradicate it, and provide some recommendations. During the past decade, a number of groups have investigated this disorder using different methodologies and reported various correlations, but failed to find a cause. Research has focussed on the contamination of water with heavy metals, agrochemicals, hard water, algae, ionicity, climate change, and so forth. Nevertheless, the levels of any of the pollutants or conditions reported in water in NPC are inconsistent not correlated with the prevalence of the disease, and are too low to be the sole cause of CKD-mfo. Meanwhile, several nephrotoxins prevalent in the region, including medications, leptospirosis, toxic herbs, illicit alcohol, locally grown tobacco, and petrochemicals, as well as the effects of changed habits occured over the past four decades have not been studied to date. Taken together, the geographical distribution and overall findings indicate that combinations of factors and/or their interactions are likely to precipitate CKD-mfo, which kills more than 5,000 people annually in Sri Lanka; most victims are middle-aged male farmers. Much anecdotal evidence from this region suggests that consumption of contaminated water is the most likely source of this deadly disease. Although the aetiology is unknown, prevention of this "environmentally acquired" disease seems relatively straightforward. Solutions include (a) preventing environmental pollution, (b) stopping the irresponsible use and decreasing the usage of agrochemicals, and encouraging the use of environmentally friendly agricultural methods, (c) taking proper precautions when using agrochemicals and safe disposal of their containers, (d) changing the risky behaviour of farmers and educating them to preserve the environment, and (e) providing clean potable water to all affected regions. Implementing a well-coordinated, in-depth, region-wide, broad-based research study together with a long-term effective surveillance programme across the country is essential to curbing this disease. Unless firm actions are taken promptly, more than three million healthy people in the country, live in agricultural regions, are at risk for contracting CKD-mfo and succumb to premature deaths, which are preventable.

Project description:Background:Chronic granulomatous disease (CGD) is a rare primary immunodeficiency of the phagocytic cells, which results in absent or diminished levels of microbicidal reactive oxygen species. The disease occurs due to germline mutations in the genes encoding the five subunits of NADPH oxidase complex. The present study is a pilot study to understand the clinical and genetic aspects of CGD in Sri Lanka. Methods:Clinical records of thirteen CGD patients were analysed and compared with similar studies performed in different countries and regions to identify patterns in demographics, clinical manifestations and infectious agents. Genomic DNA and cDNA were analysed in eight patients to identify mutations in CYBB and NCF1 genes, thereby to ascertain the potential X-linked and autosomal recessive (AR) CGD patients. Results:The onset of symptoms in the patient cohort was very early (mean 4.6 months) compared to 20 months in India and 23.9 months in Latin America. Similarly, the age at diagnosis was lower (mean 1.6 years after birth) compared to other studies; 4.5 years in India and 6.1 years in Europe. Pulmonary manifestations were the most common (85%), followed by skin/subcutaneous infections (77%) and lymphadenopathy (62%). The death rate of local patients (38%) was higher than other countries (India 35%, Europe 20%). Majority (77%) were treated for tuberculosis at some point in life. Genetic analysis confirmed six out of eight patients as X-linked CGD cases with mutations in CYBB gene. A novel splice site mutation was identified in P-07 at position c.141+6 which resulted in the deletion of entire exon 2. Two siblings (P-05 and P-06) from consanguineous parents, were identified with AR-CGD based on the homozygous GT deletion mutation in NCF1 gene. Conclusions:The clinical presentation, manifestations and genetic subtypes in the local cohort, appear to be comparable with global trends. Mycobacterial infections should be investigated and treated with more prominence. Effective treatment options are required to control the high mortality rate.

Project description:BackgroundIn Sri Lanka, there exists chronic kidney disease of both known (CKD) and unknown etiologies (CKDu). Identification of novel biomarkers that are customized to the specific causative factors would lead to early diagnosis and clearer prognosis of the diseases. This study aimed to find genetic biomarkers in blood to distinguish and identify CKDu from CKD as well as healthy populations from CKDu endemic and non-endemic areas of Sri Lanka.MethodsThe expression patterns of a selected panel of 12 potential genetic biomarkers were analyzed in blood using RT-qPCR. Fold changes of gene expressions in early and late stages of CKD and CKDu patients, and an apparently healthy population of a CKDu endemic area, Girandurukotte (GH) were calculated relative to apparently healthy volunteers from a CKDu non-endemic area, Kandy (KH) of Sri Lanka, using the comparative CT method.ResultsSignificant differences were observed between KH and early stage CKDu for both the insulin-like growth factor binding protein 1 (IGFBP1; p?=?0.012) and kidney injury molecule-1 (KIM1; p?=?0.003) genes, and KH and late stage CKD and CKDu for the glutathione-S-transferase mu 1 (GSTM1; p?<?0.05) gene. IGFBP1 and KIM1 genes showed significant difference between the early and late stage CKDu (p?<?0.01). The glutamate cysteine ligase catalytic subunit (GCLC) gene had significantly different expression between KH and all the other study groups (p?<?0.01). The GH group was significantly different from the KH group for the oxidative stress related genes, G6PD, GCLC and GSTM1 (p?<?0.01), and also the KIM1 gene (p?=?0.003). IGFBP1, insulin-like growth factor binding protein 3 (IGFBP3), fibronectin 1 (FN1) and KIM1 showed significant correlations with serum creatinine, and IGFBP1, KIM1 and kallikrein 1 (KLK1) with eGFR (p?<?0.05).ConclusionA panel consisting of IGFBP1, KIM1, GCLC and GSTM1 genes could be used in combination for early screening of CKDu, whereas these genes in addition with FN1, IGFBP3 and KLK1 could be used to monitor progression of CKDu. The regulation of these genes has to be studied on larger populations to validate their efficiency for further clinical use.

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Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka.

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Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka.

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