The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin–angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.

The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus' molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as "SARS-CoV-2," "COVID-19," "Renin Angiotensin System," "ACE2," "Angiotensin II," "Angiotensin-(1-7)," and "AT1 receptor." Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other

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Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin-angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney-brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.

Regardless the level of proteinuria, INS patients had increased expression of TNF-α in CD4-lymphocytes and reduced expression of IFN-γ in CD8-lymphocytes. Persistence of proteinuria was associated with higher levels of inflammatory markers.

Background The collapsing variant of focal segmental glomerulosclerosis (FSGS) is the most aggressive form of FSGS and is characterized by at least one glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia. Viruses can act as aetiological agents of secondary FSGS. This study aims to establish an aetiological link between dengue virus (DENV) infection and the collapsing variant of FSGS and to analyse possible influences of the apolipoprotein 1 (APOL1) gene risk alleles on the disease. Methods Biopsies and medical records were gathered from 700 patients of the Instituto de Nefropatologia, Belo Horizonte, Brazil. Screening for the collapsing variant of FSGS was performed and serological, immunohistochemical, tissue polymerase chain reaction (PCR) and genetic analysis were conducted. Results Eight patients were identified with positive DENV serology and negative serological and/or tissue markers for hepatitis B virus, hepatitis C virus, Epstein–Barr virus, human immunodeficiency virus, cytomegalovirus and parvovirus B19. In PCR analysis, six patients had positive markers for DENV strain genetic material, one patient had positive markers for co-infection of Zika virus (ZIKV) and DENV and one patient had positive markers only for ZIKV infection. Six of the eight patients did not show risk alleles of the APOL1 gene. One patient had only one risk allele (G1) and the sample from another did not contain enough DNA for genetic analysis to be performed. Conclusions This study provided strong evidence that DENV can infect renal tissue and possibly functions as a second hit to the development of the collapsing variant of FSGS. Nonetheless, this study also highlights the possible implication of ZIKV infection in FSGS and supports the argument that risk alleles of the APOL1 gene may not be implicated in the susceptibility to FSGS in these patients.

IntroductionAlzheimer’s disease (AD) is the leading cause of dementia worldwide. Despite the extensive research, its pathophysiology remains largely unelucidated. Currently, more attention is being given to the disease’s vascular and inflammatory aspects. In this context, the renin-angiotensin system (RAS) emerges as a credible player in AD pathogenesis. The RAS has multiple physiological functions, conducted by its two opposing axes: the classical, led by Angiotensin II (Ang II), and the alternative, driven by Angiotensin-(1–7) [Ang-(1–7)]. These peptides were shown to interact with AD pathology in animal studies, but evidence from humans is scarce. Only 20 studies dosed RAS molecules in AD patients’ bloodstream, none of which assessed both axes simultaneously. Therefore, we conducted a cross-sectional, case-control exploratory study to compare plasma levels of Ang II and Ang-(1–7) in AD patients vs. age-matched controls. Within each group, we searched for correlations between RAS biomarkers and measures from magnetic resonance imaging (MRI).MethodsWe evaluated patients with AD (n = 14) and aged-matched controls (n = 14). Plasma Ang II and Ang-(1–7) were dosed using ELISA. Brain MRI was performed in a 3 Tesla scan, and a three-dimensional T1-weighted volumetric sequence was obtained. Images were then processed by FreeSurfer to calculate: (1) white matter hypointensities (WMH) volume; (2) volumes of hippocampus, medial temporal cortex, and precuneus. Statistical analyses used non-parametrical tests (Mann-Whitney and Spearman).ResultsAng-(1–7) levels in plasma were significantly lower in the AD patients than in controls [median (25th–75th percentiles)]: AD [101.5 (62.43–126.4)] vs. controls [209.3 (72–419.1)], p = 0.014. There was no significant difference in circulating Ang II. In the AD patients, but not in controls, there was a positive and significant correlation between Ang-(1–7) values and WMH volumes (Spearman’s rho = 0.56, p = 0.038). Ang-(1–7) did not correlate with cortical volumes in AD or in controls. Ang II did not correlate with any MRI variable in none of the groups.ConclusionIf confirmed, our results strengthen the hypothesis that RAS alternative axis is downregulated in AD, and points to a possible interaction between Ang-(1–7) and cerebrovascular lesions in AD.