Improving predictive asthma algorithms with modelled environment data for Scotland: an observational cohort study protocol.

INTRODUCTION: Asthma has a considerable, but potentially, avoidable burden on many populations globally. Scotland has some of the poorest health outcomes from asthma. Although ambient pollution, weather changes and sociodemographic factors have been associated with asthma attacks, it remains unclear whether modelled environment data and geospatial information can improve population-based asthma predictive algorithms. We aim to create the afferent loop of a national learning health system for asthma in Scotland. We will investigate the associations between ambient pollution, meteorological, geospatial and sociodemographic factors and asthma attacks. METHODS AND ANALYSIS: We will develop and implement a secured data governance and linkage framework to incorporate primary care health data, modelled environment data, geospatial population and sociodemographic data. Data from 75 recruited primary care practices (n=500 000 patients) in Scotland will be used. Modelled environment data on key air pollutants at a horizontal resolution of 5 km×5 km at hourly time steps will be generated using the EMEP4UK atmospheric chemistry transport modelling system for the datazones of the primary care practices' populations. Scottish population census and education databases will be incorporated into the linkage framework for analysis. We will then undertake a longitudinal retrospective observational analysis. Asthma outcomes include asthma hospitalisations and oral steroid prescriptions. Using a nested case-control study design, associations between all covariates will be measured using conditional logistic regression to account for the matched design and to identify suitable predictors and potential candidate algorithms for an asthma learning health system in Scotland.Findings from this study will contribute to the development of predictive algorithms for asthma outcomes and be used to form the basis for our learning health system prototype. ETHICS AND DISSEMINATION: The study received National Health Service Research Ethics Committee approval (16/SS/0130) and also obtained permissions via the Public Benefit and Privacy Panel for Health and Social Care in Scotland to access, collate and use the following data sets: population and housing census for Scotland; Scottish education data via the Scottish Exchange of Data and primary care data from general practice Data Custodians. Analytic code will be made available in the open source GitHub website. The results of this study will be published in international peer reviewed journals.

Prorenin receptor in distal nephron segments of 2-kidney, 1-clip goldblatt hypertensive rats.

BACKGROUND: The prorenin receptor (PRR) is expressed in the kidneys and has been localized to mesangial cells, renal arterioles, and distal nephron segments. By binding renin or prorenin, this receptor increases renin catalytic activity and activates prorenin. The renin gene is expressed by the principal cells of collecting ducts and is enhanced in angiotensin II (AngII)-dependent hypertension and in both kidneys of 2-kidney, 1-clip (2K1C) Goldblatt hypertensive rats. Colocalization of PRR with prorenin and renin in distal nephron segments may contribute to increased local AngII formation. METHODS: We examined the specific cell-type localization of PRR in distal nephron segments and the changes in PRR gene expression in both kidneys of 2K1C hypertensive rats (n=6) and sham-operated rats (n=5). RESULTS: After 25 days, systolic blood pressure and plasma renin activity increased to 186 ± 8 mmHg and 12.8 ± 3 ng/AngI/mL/hr, respectively, in 2K1C rats compared to controls (133 ± 9 mmHg and 7.1 ± 1 ng/AngI/mL/hr, respectively). Immunohistochemistry of the PRR on fixed kidney sections showed intense positive staining in the apical aspects of intercalated cells in collecting ducts. PRR immunoreactivity (clipped kidney: 2.3 ± 1 IDU; nonclipped kidney: 1.3 ± 0 IDU; sham: 1.0 ± 0.0 IDU; P<0.05) and messenger RNA levels measured by quantitative real-time polymerase chain reaction (clipped kidney: 1.3 ± 0.1 au; nonclipped kidney: 0.9 ± 0.3 au; sham: 1 ± 0.0 au; P<0.05] were increased in collecting duct cells of clipped kidneys of 2K1C rats compared to nonclipped and sham kidneys. CONCLUSION: The enhanced renin gene expression in the collecting ducts of hypertensive rats suggests that the renin secreted by principal cells is then anchored by the PRR on the intercalated cells, thus contributing to increased angiotensin peptide generation in distal nephron segments.

Enhancement of renin and prorenin receptor in collecting duct of Cyp1a1-Ren2 rats may contribute to development and progression of malignant hypertension.

To determine whether in the transgenic rat model [TGR(Cyp1a1Ren2)] with inducible ANG II-dependent malignant hypertension changes in the activation of intrarenal renin-angiotensin system may contribute to the pathogenesis of hypertension, we examined the gene expression of angiotensinogen (AGT) in renal cortical tissues and renin and prorenin receptor [(P)RR] in the collecting duct (CD) of the kidneys from Cyp1a1Ren2 rats (n = 6) fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days and noninduced rats maintained on a normal diet (0.6% NaCl diet; n = 6). Rats induced with I3C developed malignant hypertension and exhibited alterations in the expression of renin and (P)RR expressed by the CD cells. In the renal medullary tissues of the Cyp1a1Ren2 transgenic rats with malignant hypertension, renin protein levels in CD cells were associated with maintained renin content and lack of suppression of the endogenous Ren1c gene expression. Furthermore, these tissues exhibited increased levels of (P)RR transcript, as well as of the protein levels of the soluble form of this receptor, the s(P)RR. Intriguingly, although previous findings demonstrated that urinary AGT excretion is augmented in Cyp1a1Ren2 transgenic rats with malignant hypertension, in the present study we did not find changes in the gene expression of AGT in renal cortical tissues of these rats. The data suggest that upregulation of renin and the s(P)RR in the CD, especially in the renal medullary tissues of Cyp1a1Ren2 transgenic rats with malignant hypertension, along with the previously demonstrated increased availability of AGT in the urine of these rats, may constitute a leading mechanism to explain elevated formation of kidney ANG II levels in this model of ANG II-dependent hypertension.