Association between urinary glyphosate levels and serum neurofilament light chain in a representative sample of US adults: NHANES 2013-2014.

BACKGROUND: Glyphosate, the herbicide with the highest global usage, has been found to have links to neurological impairment in some occupational studies. Neurofilament light chain (NfL) is a protein that is released into the bloodstream following neuroaxonal damage and has emerged as a reliable biomarker for various neurological disorders. However, no research has investigated the potential link between glyphosate exposure and neurological damage or serum NfL levels in the general population. OBJECTIVE: The objective of this study was to assess the possible correlation between glyphosate exposure and serum NfL levels in a population that is representative of the United States. METHODS: We analyzed data from 597 adults (aged ≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the potential correlation between urinary glyphosate levels and serum NfL levels. RESULTS: We found a significant positive association between urinary glyphosate levels and serum NfL levels (ß-coefficient = 0.110; S.E. = 0.040; P = 0.015), indicating that higher levels of glyphosate exposure may be linked to higher levels of neuroaxonal damage. Furthermore, when glyphosate levels were divided into quintiles, we observed a significant trend of increasing mean NfL concentrations with increasing quintiles of glyphosate exposure (P for trend = 0.036). Notably, the association was more pronounced in certain subgroups, including those aged ≥40 years, non-Hispanic whites, and those with a BMI between 25 and 30. IMPACT STATEMENT: This is the first research to suggest an association between glyphosate exposure and biomarkers indicative of neurological damage in general U.S. adults. If the correlation observed is causal, it raises concerns about the potential effects of glyphosate exposure on neurological health among U.S. adults. The study is noteworthy due to its representation of American adults aged 20 and above, as well as the use of reliable and comprehensive data from the NHANES database.

Association between Glyphosate Exposure and Erythrograms in a Representative Sample of US Adults: NHANES 2013-2014.

Glyphosate is the most commonly utilized herbicide globally, and a growing body of experimental research has linked its exposure to red blood cell damage. However, the potential toxicity of glyphosate exposure on erythrocytes in the general population remains poorly understood. Therefore, we analyzed data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) of 1466 adults (≥ 18 years) to explore the potential relationship between glyphosate exposure and erythrocyte profiles. Our results indicated a significant negative association between urinary glyphosate levels and hemoglobin (Hb) and hematocrit (Hct) in multiple regression analysis, with ß coefficients of -0.157 (S.E. = 0.055, P = 0.012) and -0.431 (S.E. = 0.195, P = 0.043), respectively. Additionally, the odds ratio showed a significant increase in individuals with anemia with a one-unit increase in ln-glyphosate levels (odds ratio = 1.523 (95% CI = 1.301 - 1.783), P < 0.001 in the final model). The negative correlation between glyphosate and Hb was more pronounced in subjects older than 60 years, non-Hispanic white ethnicity, lower income, and those with a body mass index (BMI) < 25 and ≥ 30. In conclusion, our results provide preliminary evidence of a plausible association between glyphosate exposure and anemia in a subset of the adult population in the United States. However, further research is necessary to understand the underlying mechanisms and clinical implications of this association.

Collectrin (Tmem27) deficiency in proximal tubules causes hypertension in mice and a TMEM27 variant associates with blood pressure in males in a Latino cohort.

Collectrin (Tmem27), an angiotensin-converting enzyme 2 homologue, is a chaperone of amino acid transporters in the kidney and endothelium. Global collectrin knockout (KO) mice have hypertension, endothelial dysfunction, exaggerated salt sensitivity, and diminished renal blood flow. This phenotype is associated with altered nitric oxide and superoxide balance and increased proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) expression. Collectrin is located on the X chromosome where genome-wide association population studies have largely been excluded. In the present study, we generated PT-specific collectrin KO (PT KO) mice to determine the precise contribution of PT collectrin in blood pressure homeostasis. We also examined the association of human TMEM27 single-nucleotide polymorphisms with blood pressure traits in 11,926 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Hispanic/Latino participants. PT KO mice exhibited hypertension, and this was associated with increased baseline NHE3 expression and diminished lithium excretion. However, PT KO mice did not display exaggerated salt sensitivity or a reduction in renal blood flow compared with control mice. Furthermore, PT KO mice exhibited enhanced endothelium-mediated dilation, suggesting a compensatory response to systemic hypertension induced by deficiency of collectrin in the PT. In HCHS/SOL participants, we observed sex-specific single-nucleotide polymorphism associations with diastolic blood pressure. In conclusion, loss of collectrin in the PT is sufficient to induce hypertension, at least in part, through activation of NHE3. Importantly, our model supports the notion that altered renal blood flow may be a determining factor for salt sensitivity. Further studies are needed to investigate the role of the TMEM27 locus on blood pressure and salt sensitivity in humans.NEW & NOTEWORTHY The findings of our study are significant in several ways: 1) loss of an amino acid chaperone in the proximal tubule is sufficient to cause hypertension, 2) the results in global and proximal tubule-specific collectrin knockout mice support the notion that vascular dysfunction is required for salt sensitivity or that impaired renal tubule function causes hypertension but is not sufficient to cause salt sensitivity, and 3) our study is the first to implicate a role of collectrin in human hypertension.

Trends of medication used in patients with pre-ESKD from 2010 to 2018 in Taiwan.

BACKGROUND/PURPOSE: The burden of end-stage kidney disease (ESKD) continues to grow globally. Information on medication prescribed to advanced chronic kidney disease (CKD) patients can help formulate further CKD prevention policies. This study aimed to review and assess several major medications routinely prescribed to pre-ESKD patients. METHODS: Medication information of advanced CKD patients one year before regular dialysis was collected from the National Health Insurance Research Database from 2000 to 2018 in Taiwan. Usages of major medication were comprehensively analyzed. RESULTS: During 2000-2018, trends in medication usage evolved gradually in the pre-ESKD population in Taiwan. The use of erythropoietin had increased (48.3% in 2000 to 71.0% in 2018) with decreased blood transfusion rate (70.9% in 2003 to 52.1% in 2018). The use of non-steroidal anti-inflammatory drugs had also dropped (43.5% in 2004 to 25.5% in 2018). These changes were more evident for patients enrolled in the pre-ESKD prevention program. The most frequently used blood pressure-lowering and glucose-lowering agents were calcium channel blockers (90.6%) and insulin (78.1%), but usage of metformin was unexpectedly high (38.4% in 2018). The most frequently used blood thinner was aspirin (49.5%), with considerably increased use of direct oral anticoagulant (16.5% in 2018). CONCLUSION: An overview of the trends of major medication usage and blood transfusion represented the continuously improving care quality in pre-ESKD patients in Taiwan. These trends were especially evident in patients enrolled in the pre-ESKD prevention program. This report also indirectly indicated the potential and long-term benefits of implementing CKD and pre-ESKD prevention programs.

Apoptotic microparticles mediate the association between bisphenol A and subclinical atherosclerosis in a young population: A population-based study.

Bisphenol A (BPA) exposure is associated with atherosclerotic cardiovascular diseases. The interactions between BPA, extracellular microparticles (MPs), and atherosclerosis are unknown. A total of 103,756 young students participated in the mass urine-screening program in Taiwan between 1992 and 2000 were analyzed. After exclusion, 886 subjects were recruited to test the relationships between serum level of BPA, endothelial and platelet MPs as well as subclinical atherosclerosis represented by carotid artery intima-media thickness (CIMT). We found that an increment of one unit of log-BPA could lead to significant association between thicker CIMT and concentrations of endothelial microparticles and platelet microparticles in the cohort (odds ratio (OR) 1.23, P < 0.001). CD31 + /CD42a- (> 50%, OR 1.229, P = 0.001) and CD31 + /CD42a+ (≦ 50%, OR 1.262, P = 0.017 and > 50%, OR 1.212, P = 0.006) were significantly associated with thicker CIMT in the presence of elevated BPA. When considering the interactions between CD31 + /CD42a- and CD31 + /CD42a+ , we observed increased OR as CD31 + /CD42a- was greater than 50% (CD31 +/CD42a- > 50% and CD31 +/CD42a+ ≦ 50%, OR 1.356, P = 0.029; CD31 +/CD42a- > 50% and CD31 +/CD42a+ > 50%, OR 1.204, P = 0.014). Our study identified a higher risk of thicker CIMT associated with altered MPs in the presence of elevated BPA levels. BPA exposure is associated with endothelial dysfunction and subclinical atherosclerosis in a young population.

The ratio and difference of urine protein-to-creatinine ratio and albumin-to-creatinine ratio facilitate risk prediction of all-cause mortality.

The role of the difference and ratio of albuminuria (urine albumin-to-creatinine ratio, uACR) and proteinuria (urine protein-to-creatinine ratio, uPCR) has not been systematically evaluated with all-cause mortality. We retrospectively analyzed 2904 patients with concurrently measured uACR and uPCR from the same urine specimen in a tertiary hospital in Taiwan. The urinary albumin-to-protein ratio (uAPR) was derived by dividing uACR by uPCR, whereas urinary non-albumin protein (uNAP) was calculated by subtracting uACR from uPCR. Conventional severity categories of uACR and uPCR were also used to establish a concordance matrix and develop a corresponding risk matrix. The median age at enrollment was 58.6 years (interquartile range 45.4-70.8). During the 12,391 person-years of follow-up, 657 deaths occurred. For each doubling increase in uPCR, uACR, and uNAP, the adjusted hazard ratios (aHRs) of all-cause mortality were 1.29 (95% confidence interval [CI] 1.24-1.35), 1.12 (1.09-1.16), and 1.41 (1.34-1.49), respectively. For each 10% increase in uAPR, it was 1.02 (95% CI 0.98-1.06). The linear dose-response association with all-cause mortality was only observed with uPCR and uNAP. The 3 × 3 risk matrices revealed that patients with severe proteinuria and normal albuminuria had the highest risk of all-cause mortality (aHR 5.25, 95% CI 1.88, 14.63). uNAP significantly improved the discriminative performance compared to that of uPCR (c statistics: 0.834 vs. 0.828, p-value = 0.032). Our study findings advocate for simultaneous measurements of uPCR and uACR in daily practice to derive uAPR and uNAP, which can provide a better mortality prognostic assessment.

Association between acrylamide exposure and sex hormones in males: NHANES, 2003-2004.

INTRODUCTION: Acrylamide is widely present in heat-processed food, cigarette smoke and environment. Reproductive toxicity was reported in animals treated with acrylamide, particularly in males. The reproductive toxicity of acrylamide and its active metabolite, glycidamide, was reported to be mainly mediated through DNA damage in spermatocytes. However, the effect of acrylamide on sex hormones in men is unknown. METHODS: There were 468 male subjects (age ≧ 12 years) enrolled to determine the relationships between hemoglobin adducts of acrylamide (HbAA) and hemoglobin adducts of glycidamide (HbGA) with several sex hormones using the National Health and Nutrition Examination Survey (NHANES), 2003 to 2004. All potential confounding variables in the data set were properly adjusted. RESULTS: We found that one unit increase in the natural log-transformed HbAA level was associated with an increase in natural log transformed serum inhibin B level by 0.10 (SE = 0.05; P = 0.046), and natural log transformed serum sex hormone binding globulin (SHBG) by 0.15 (SE = 0.15; P = 0.036). With respect to HbGA, one unit increase in the natural log-transformed HbGA level was associated with an increase in natural log transformed serum anti-Müllerian Hormone (AMH) level by 0.31 (SE = 0.00; P = 0.003). CONCLUSION: In this representative cohort, we identified positive associations between acrylamide exposure and several sex hormones in men. The HbAA is positively associated with inhibin B and SHBG, and HbGA is positively associated with AMH. Other than genotoxicity, our findings suggested that altered sex hormones might also play a role in acrylamide-related reproductive toxicity in males.

Joint Longitudinal Low Calcium High Phosphorus Trajectory Associates with Accelerated Progression, Acute Coronary Syndrome and Mortality in Chronic Kidney Disease.

The effects of long-term disturbance of the mineral metabolism on patients with chronic kidney disease (CKD) are unclear. We investigated whether the longitudinal Ca-P (joint calcium and phosphorus) trajectories are associated with incident end-stage renal disease (ESRD), acute coronary syndrome (ACS), and all-cause mortality in patients with CKD. We conducted a prospective cohort study by using data from a 13-year multidisciplinary pre-ESRD care registry. The final study population consisted of 4,237 CKD patients aged 20-90 years with data gathered from 2003 to 2015. Individuals' Ca-P trajectories were defined using group-based multi-trajectory modeling into three distinct patterns: reference, moderately abnormal, and severely abnormal. Times to ESRD, ACS, and death were analyzed using multiple Cox regression. Compared with those with a "reference" Ca-P trajectory, the adjusted hazard ratios (aHRs) (95% confidence interval [CI]) for incidental ESRD were 5.92 (4.71-7.44) and 15.20 (11.85-19.50) for "moderately abnormal" and "severely abnormal" Ca-P trajectories, respectively. The corresponding aHRs for ACS were 1.94 (1.49-2.52) and 3.18 (2.30-4.39), and for all-cause mortality, they were 1.88 (1.64-2.16) and 2.46 (2.05-2.96) for "moderately abnormal" and "severely abnormal" Ca-P trajectories, respectively. For outcomes of progression to ESRD, the detrimental effects of abnormal Ca-P trajectories were more substantial in patients with CKD stage 3 than those with CKD stage 4 or 5 (p-value for interaction < 0.001). Future studies should validate reliable longitudinal cut-offs of serum phosphorus and consider the "lowering phosphorus- the lower the better, the earlier the better" approach to phosphorus control in CKD.

Dialysis timing may be deferred toward very late initiation: An observational study.

The optimal timing to initiate dialysis among patients with an estimated glomerular filtration rate (eGFR) of <5 mL/min/1.73 m2 is unknown. We hypothesized that dialysis initiation time can be deferred in this population even with high uremic burden. A case-crossover study with case (0-30 days before dialysis initiation [DI]) and control (90-120 days before DI) periods was conducted in 1,079 hemodialysis patients aged 18-90 years at China Medical University Hospital between 2006 and 2015. The uremic burden was quantified based on 7 uremic indicators that reached the predefined threshold in case period, namely hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate. Dialysis timing was classified as standard (met 0-2 uremic indicators), late (3-5 indicators), and very late (6-7 indicators). Median eGFR-DI of the 1,079 patients was 3.4 mL/min/1.73 m2 and was 2.7 mL/min/1.73 m2 in patients with very late initiation. The median follow-up duration was 2.42 years. Antibiotics, diuretics, antihypertensive medications, and non-steroidal anti-inflammatory drugs (NSAIDs) were more prevalently used during the case period. The fully adjusted hazards ratios of all-cause mortality for the late and very late groups were 0.97 (95% confidence interval 0.76-1.24) and 0.83 (0.61-1.15) compared with the standard group. It is safe to defer dialysis initiation among patients with chronic kidney disease (CKD) having an eGFR of <5 mL/min/1.73 m2 even when patients having multiple biochemical uremic burdens. Coordinated efforts in acute infection prevention, optimal fluid management, and prevention of accidental exposure to NSAIDs are crucial to prolong the dialysis-free survival.

24-hour Serum Creatinine Variation Associates with Short- and Long-Term All-Cause Mortality: A Real-World Insight into Early Detection of Acute Kidney Injury.

Real-world evidence describing the variation in serum creatinine (S-Cre) within 24 hours and its prognostic value is unknown. We enrolled 14 912 adults who received two S-Cre measurements within 24 hours at a tertiary hospital between 2003 and 2016. The study population was divided into four groups according to the hospital service settings where the baseline and second S-Cre were measured: Group 1, Outpatient-to-Outpatient; Group 2, Outpatient-to-ED (emergency department) or Inpatient; Group 3, ED-to-ED or Inpatient; and Group 4, Inpatient-to-Inpatient. The main predictors were the difference between the two S-Cre measurements (ΔS-Cre) and the percent change (ΔS-Cre%). The main outcomes were 30-day, 1-year, or 3-year all-cause mortality. A total of 6753 and 8159 patients with an increase and a decrease within-day ΔS-Cre, respectively. Among 6753 patients who had deteriorating ΔS-Cre or ΔS-Cre%, the adjusted hazard ratio (aHR) for 1-year all-cause mortality for each 0.1 mg/dL or 5% change in S-Cre was 1.09 (95% confidence interval [CI]: 1.07, 1.11) and 1.03 (95% CI: 1.03, 1.04). In 8159 patients with improving ΔS-Cre%, the aHR was 0.97 (95% CI: 0.94, 1.00). Groups 3 and 4 had statistically significant positive linear relationships between deteriorating ΔS-Cre% and 30-day and 3-year mortality. The optimal cut-offs for deteriorating ΔS-Cre% for predicting 30-day mortality were approximately 22% for Group 3 and 20% for Group 4. Inpatient within-day deteriorating ΔS-Cre or ΔS-Cre% above 0.2 mg/dL or 20%, respectively, is associated with all-cause mortality. Monitoring 24-hour S-Cre variation identifies acute kidney injury earlier than the conventional criteria.

Longitudinal lipid trends and adverse outcomes in patients with CKD: a 13-year observational cohort study.

Studies on the effects of longitudinal lipid trajectories on end-stage renal disease (ESRD) development and deaths among patients with chronic kidney disease (CKD) are limited. We conducted a registry-based prospective study using data from a 13-year multidisciplinary pre-ESRD care program. The final study population comprised 4,647 patients with CKD. Using group-based trajectory modeling, we dichotomized longitudinal trajectories of total cholesterol (T-CHO), triglyceride (TG), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C). Time to ESRD or death was analyzed using multiple Cox regression. At baseline, higher levels of T-CHO and LDL-C were associated with rapid progression to ESRD, whereas only HDL-C was positively associated with all-cause mortality [adjusted hazard ratio (HR), 1.20; 95% CI, 1.06-1.36; P-value, 0.005]. Compared with those with a normal T-CHO trajectory, the fully adjusted HR of patients with a high T-CHO trajectory for ESRD risk was 1.21 (P-value, 0.019). Subgroup analysis showed that a high TG trajectory was associated with a 49% increase in mortality risk in CKD patients without diabetes (P-value for interaction, 0.012). In contrast to what was observed based on baseline HDL-C, patients with a trajectory of frequent hypo-HDL cholesterolemia had higher risk of all-cause mortality (adjusted HR, 1.53; P-value, 0.014). Thus, only T-CHO, both at baseline and over the longitudinal course, demonstrated a significant potential risk of incident ESRD. The inconsistency in the observed directions of association between baseline levels and longitudinal trajectories of HDL-C warrants further research to unveil specific pathogenic mechanisms underlying the HDL-C metabolism in patients with CKD.

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Association among total serum isomers of perfluorinated chemicals, glucose homeostasis, lipid profiles, serum protein and metabolic syndrome in adults: NHANES, 2013-2014.

Perfluorinated chemicals (PFCs) have been used widely in consumer products manufacture. Recent in vitro as well as animal studies have found that there are different toxicity and pharmacokinetic profiles between isomers of perfluorooctanoic acid (PFOA) and/or perfluorooctane sulfonate (PFOS). However, the differential effects of linear or branched PFOA/PFOS isomers on human beings have never been reported. Herein, we examined 1871 adult subjects (age older than 18 years) from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 to determine the association between the isomers of PFOA/PFOS and serum biochemistry profiles, including glucose, lipids, protein and components of metabolic syndrome (MS). The results showed that for PFOA, increased linear PFOA was associated with increases in total cholesterol, serum albumin and an enhancement of ß cell function as well as a decrease in the serum globulin. Increased branched PFOA was significantly associated with increased fasting glucose. All isomers of PFOA were positively associated with high-density lipoprotein-cholesterol (HDL-C) and negatively associated with glycohemoglobin (HbA1C). The branched PFOS was positively associated with ß cell function and inversely associated with serum globulin. Both linear and branched isomers of PFOS were positively associated with the total protein and albumin. The increased branched PFOA was associated with less HDL-C insufficiency defined by the National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATP III) MS criteria, whereas the increased concentrations of serum total and linear PFOS were associated with less hypertriglyceridemia by the NCEP-ATP III. In conclusion, serum isomers of PFOA and PFOS were associated with glucose homeostasis, serum protein as well as lipid profiles; they were also indicators of MS. This may suggest that there is a distinct difference in the toxicokinetics of the isomers of PFOA and PFOS. Further clinical and animal studies are warranted to clarify the putative causal relationships between isomers and biochemical alterations.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II.

Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.

ACE2 and the Homolog Collectrin in the Modulation of Nitric Oxide and Oxidative Stress in Blood Pressure Homeostasis and Vascular Injury.

SIGNIFICANCE: Hypertension is the leading risk factor causing mortality and morbidity worldwide. Angiotensin (Ang) II, the most active metabolite of the renin-angiotensin system, plays an outstanding role in the pathogenesis of hypertension and vascular injury. Activation of angiotensin converting enzyme 2 (ACE2) has shown to attenuate devastating effects of Ang II in the cardiovascular system by reducing Ang II degradation and increasing Ang-(1-7) generation leading to Mas receptor activation. Recent Advances: Activation of the ACE2/Ang-(1-7)/Mas receptor axis reduces hypertension and improves vascular injury mainly through an increased nitric oxide (NO) bioavailability and decreased reactive oxygen species production. Recent studies reported that shedding of the enzymatically active ectodomain of ACE2 from the cell surface seems to regulate its activity and serves as an interorgan communicator in cardiovascular disease. In addition, collectrin, an ACE2 homolog with no catalytic activity, regulates blood pressure through an NO-dependent mechanism. CRITICAL ISSUES: Large body of experimental data confirmed sustained beneficial effects of ACE2/Ang-(1-7)/Mas receptor axis activation on hypertension and vascular injury. Experimental studies also suggest that activation of collectrin might be beneficial in hypertension and endothelial dysfunction. Their role in clinical hypertension is unclear as selective and reliable activators of both axes are not yet available. FUTURE DIRECTIONS: This review will highlight the results of recent research progress that illustrate the role of both ACE and collectrin in the modulation of NO and oxidative stress in blood pressure homeostasis and vascular injury, providing evidence for the potential therapeutic application of ACE2 and collectrin in hypertension and vascular disease. Antioxid. Redox Signal. 26, 645-659.

Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.

Role of collectrin, an ACE2 homologue, in blood pressure homeostasis.

Collectrin (Tmem27) is a transmembrane glycoprotein that is highly expressed in the kidney and vascular endothelium. It is a homologue of the angiotensin-converting enzyme 2 (ACE2) but harbors no catalytic domain. In the extravascular tissues of the kidney, collectrin is localized to the proximal tubule and collecting duct. Collectrin-deficient mice are featured with hypertension and exaggerated salt sensitivity. These phenotypes are associated with impaired uptake of the nitric oxide precursor L-arginine and the expression of its amino acid transporters, CAT-1 and y(+)LAT1, in endothelial cells. In addition, collectrin-deficient mice display decreased dimerization of nitric oxide synthase and decreased nitric oxide synthesis, but enhanced superoxide generation, suggesting that deletion of collectrin leads to a state of nitric oxide synthase uncoupling. These findings suggest that collectrin plays a protective role against hypertension. The collectrin knockout mouse represents a unique model for hypertension research. Furthermore, collectrin may serve as a novel therapeutic target in the treatment of hypertension.