The RenTg Mice: A Powerful Tool to Study Renin-Dependent Chronic Kidney Disease

Background

Several studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD.

Methodology/Principal Findings

We used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFβ family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation.

Conclusions/Significance

The RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease.     

Reading and Visual Search: A Developmental Study in Normal Children

Studies dealing with developmental aspects of binocular eye movement behaviour during reading are scarce. In this study we have explored binocular strategies during reading and during visual search tasks in a large population of normal young readers. Binocular eye movements were recorded using an infrared video-oculography system in sixty-nine children (aged 6 to 15) and in a group of 10 adults (aged 24 to 39). The main findings are (i) in both tasks the number of progressive saccades (to the right) and regressive saccades (to the left) decreases with age; (ii) the amplitude of progressive saccades increases with age in the reading task only; (iii) in both tasks, the duration of fixations as well as the total duration of the task decreases with age; (iv) in both tasks, the amplitude of disconjugacy recorded during and after the saccades decreases with age; (v) children are significantly more accurate in reading than in visual search after 10 years of age. Data reported here confirms and expands previous studies on children''s reading. The new finding is that younger children show poorer coordination than adults, both while reading and while performing a visual search task. Both reading skills and binocular saccades coordination improve with age and children reach a similar level to adults after the age of 10. This finding is most likely related to the fact that learning mechanisms responsible for saccade yoking develop during childhood until adolescence.     

Molecular and genomic characterisation of a panel of human anal cancer cell lines

Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.Subject terms: Targeted therapies, Anal cancer, Immune evasion, Cancer models     

Restoration of Podocyte Structure and Improvement of Chronic Renal Disease in Transgenic Mice Overexpressing Renin

Background

Proteinuria is a major marker of the decline of renal function and an important risk factor of coronary heart disease. Elevated proteinuria is associated to the disruption of slit-diaphragm and loss of podocyte foot processes, structural alterations that are considered irreversible. The objective of the present study was to investigate whether proteinuria can be reversed and to identify the structural modifications and the gene/protein regulation associated to this reversal.

Methodology/Principal Findings

We used a novel transgenic strain of mouse (RenTg) that overexpresses renin at a constant high level. At the age of 12-month, RenTg mice showed established lesions typical of chronic renal disease such as peri-vascular and periglomerular inflammation, glomerular ischemia, glomerulosclerosis, mesangial expansion and tubular dilation. Ultrastructural analysis indicated abnormal heterogeneity of basement membrane thickness and disappearance of podocyte foot processes. These structural alterations were accompanied by decreased expressions of proteins specific of podocyte (nephrin, podocin), or tubular epithelial cell (E-cadherin and megalin) integrity. In addition, since TGFβ is considered the major pro-fibrotic agent in renal disease and since exogenous administration of BMP7 is reported to antagonize the TGFβ-induced phenotype changes in kidney, we have screened the expressions of several genes belonging in the TGFβ/BMP superfamily. We found that the endogenous inhibitors of BMPs such as noggin and Usag-1 were several-fold activated inhibiting the action of BMPs and thus reinforcing the deleterious action of TGFβ.Treatment with an AT1 receptor antagonist, at dose that did not decrease arterial pressure, gradually reduced albuminuria. This decrease was accompanied by re-expression of podocin, nephrin, E-cadherin and megalin, and reappearance of podocyte foot processes. In addition, expressions of noggin and Usag-1 were markedly decreased, permitting thus activation of the beneficial action of BMPs.

Conclusions/Significance

These findings show that proteinuria and alterations in the expression of proteins involved in the integrity and function of glomerular and renal epithelial phenotype are reversible events when the local action of angiotensin II is blocked, and provide hope that chronic renal disease can be efficiently treated.     

HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm,Sweden: A registry-based cohort study

BackgroundThe relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality.Methods and findingsThis cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins.In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%).A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens.ConclusionsStatin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.

In this cohort study, Rita Bergqvist and colleagues investigate the relationship between statin treatment and COVID-19 mortality.     

Postural control during the Stroop test in dyslexic and non dyslexic teenagers

Postural control in quiet stance although simple still requires some cognitive resources; dual cognitive tasks influence further postural control. The present study examines whether or not dyslexic teenagers experience postural instability when performing a Stroop dual task for which their performances are known to be poor. Fifteen dyslexics and twelve non-dyslexics (14 to 17 years old) were recruited from the same school. They were asked to perform three tasks: (1) fixate a target, (2) perform an interference Stroop test (naming the colour or the word rather than reading the word), (3) performing flexibility Stroop task: the subject performed the interference task as in (2) except when the word was in a box, in which case he had to read the word. Postural performances were measured with a force platform. The results showed a main task effect on the variance of speed of body sway only: such variance was higher in the flexibility task than for the other two tasks. No group effect was found for any of the parameters of posture (surface, mediolateral and anteroposterior sway, variance of speed). Further wavelet analysis in the time-frequency domain revealed an increase in the spectral power of the medium frequency range believed to be related to cerebellum control; an accompanying increase in the cancellation time of the high frequency band related to reflexive loops occurred for non-dyslexics only. These effects occurred for the flexibility task and could be due to its high cognitive difficulty. Dyslexics displayed shorter cancellation time for the medium frequency band for all tasks, suggesting less efficient cerebellar control, perhaps of eye fixation and attention influencing body sway. We conclude that there is no evidence for a primary posture deficit in 15 year old teenagers who come from the general population and who were recruited in schools.