An evaluation of renin‐angiotensin system markers in youth with type 2 diabetes and associations with renal outcomes

Dart, Allison; Wicklow, Brandy; Scholey, James W.; Sellers, Elizabeth; Dyck, Justin; Mahmud, Farid H; Sochett, Etienne; Hamilton, Jill; Blydt‐Hansen, Tom; Burns, Kevin D.

doi:10.1111/pedi.13081

Cited by 9 publications

(11 citation statements)

References 41 publications

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“…Measures of intra-renal RAS activity and systemic RAS activity may not always be concordant, as noted in studies by Brenner and coworkers [ 64 ]. We have also found inconsistencies between systemic and renal measures of the RAAS in our recent studies of youth with type 2 diabetes that limit interpretation [ 65 ]. Serfero et al have suggested that the production of Ang-(1–7) from Ang II in the circulation is independent of ACE2 [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

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Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

2021

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Background Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. Methods We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. Results ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. Conclusions Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

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Section: Discussionmentioning

confidence: 99%

“…65, P < 0.0001; Fig8A) in men, but the relationship was not significant in females (r = -0.29, P = 0.08; Fig8B). Our analysis showed a similar difference between males and females in the relationship between ACE2 expression and CCL2 expression (Fig 8Cand 8D).…”

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confidence: 90%

Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

2021

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“…However, there is no direct evidence that recombinant ACE2 binds and neutralizes SARS-CoV-2. Patients with hypertension, diabetes, or obesity present the major risk group for COVID-19 and are characterized by high levels of sACE2 [ 11 , 12 , 13 , 14 ]. These findings suggest that sACE2 is unable to bind and neutralize SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

OM-85 Broncho-Vaxom®, a Bacterial Lysate, Reduces SARS-CoV-2 Binding Proteins on Human Bronchial Epithelial Cells

et al. 2021

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In clinical studies, OM-85 Broncho-Vaxom®, a bacterial lysate, reduced viral respiratory tract infection. Infection of epithelial cells by SARS-CoV-2 depends on the interaction of its spike-protein (S-protein) with host cell membrane proteins. In this study, we investigated the effect of OM-85 on the expression of S-protein binding proteins by human bronchial epithelial cells. Human bronchial epithelial cells were treated with OM-85 over 5 days. The expression of SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), transmembrane protease serine subtype 2 (TMPRSS2), dipeptidyl peptidase-4 (DPP4), and a disintegrin and metalloprotease 17 (ADAM17) were determined by Western blotting and quantitative RT-PCR. Soluble (s)ACE2, heparan sulfate, heparanase, and hyaluronic acid were assessed by ELISA. OM-85 significantly reduced the expression of ACE2 (p < 0.001), TMPRSS2 (p < 0.001), DPP4 (p < 0.005), and cellular heparan sulfate (p < 0.01), while ADAM17 (p < 0.02) expression was significantly upregulated. Furthermore, OM-85 increased the level of sACE2 (p < 0.05), hyaluronic acid (p < 0.002), and hyaluronan synthase 1 (p < 0.01). Consequently, the infection by a SARS-CoV-2 spike protein pseudo-typed lentivirus was reduced in cells pretreated with OM-85. All effects of OM-85 were concentration- and time-dependent. The results suggest that OM-85 might reduce the binding of SARS-CoV-2 S-protein to epithelial cells by modification of host cell membrane proteins and specific glycosaminoglycans. Thus, OM-85 might be considered as an add-on for COVID-19 therapy.

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“…Renal injury is a frequent complication in adolescents with type 2 diabetes 30 31 and predicts long-term chronic kidney disease. 32 Significant weight loss, secondary to bariatric surgery, is associated with resolution of proteinuria in adolescents with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Physical activity and cardiometabolic health in adolescents with type 2 diabetes: a cross-sectional study

Slaght

Wicklow

Dart

et al. 2021

BMJ Open Diab Res Care

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IntroductionYouth living with type 2 diabetes display increased risk of cardiovascular disease (CVD). It is unclear if regular physical activity (PA) modifies this risk.Research design and methodsWe compared CVD risk factors in a cross-sectional study of 164 youth with type 2 diabetes stratified according to weekly vigorous-intensity PA. Outcomes were hemoglobin A1c (HbA1c), ambulatory blood pressure (BP; ambulatory 24-hour readings), plasma lipoproteins, and albuminuria. The main exposure, vigorous-intensity PA, was quantified with the Adolescent Physical Activity Recall Questionnaire.ResultsYouth were 15±3 years, and 78% lived rurally and 68% were female, with a mean body mass index (BMI) Z-score of 2.4±1.1 and a mean HbA1c of 9.6% ±2.6%. Youth who participated in regular vigorous-intensity PA (40%; n=67) achieved nearly twice the dose of PA than peers who did not (62 vs 34 metabolic equivalent score-hour/week, p=0.001). After adjusting for duration of diabetes, BMI Z-score, sex, and smoking, youth who engaged in vigorous-intensity PA displayed lower HbA1c (9.1% vs 9.9%, p=0.052), diastolic BP (70 mm Hg vs 73 mm Hg, p=0.002), diastolic load (20% vs 26%, p=0.023), and mean arterial pressure (87.3 mm Hg vs 90.3 mm Hg, p<0.01), compared with youth who did not. Compared with youth who did not participate in regular vigorous-intensity PA, those who did also displayed lower odds of albuminuria after adjusting for duration of diabetes, sex, smoking, rural residence, and BMI Z-score (adjusted OR: 0.40, 95% CI 0.19 to 0.84).ConclusionsAmong youth with type 2 diabetes, participation in vigorous-intensity PA is associated with lower CVD risk.

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An evaluation of renin‐angiotensin system markers in youth with type 2 diabetes and associations with renal outcomes

Cited by 9 publications

References 41 publications

Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

OM-85 Broncho-Vaxom®, a Bacterial Lysate, Reduces SARS-CoV-2 Binding Proteins on Human Bronchial Epithelial Cells

Physical activity and cardiometabolic health in adolescents with type 2 diabetes: a cross-sectional study

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