Who and where is the renal baroreceptor?: the connexin hypothesis

Gap junctions are emerging as a fundamental mechanism for the control of renin synthesis and release. Connexin40 is prominent in juxtaglomerular cells. When missing, it results in hyperreninemia and hypertension. Schweda et al. offer exciting data demonstrating that connexin45, a connexin with different biophysical properties, can replace connexin40 functions related to the control of renin

Protein Kinase G Is Involved in Acute but Not in Long-Term Regulation of Renin Secretion

Pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) is, in combination with diuretics, the first-choice treatment for hypertension, although 10-20% of patients do not respond adequately. Next to the RAAS, the nitric oxide/cGMP/protein kinase G (PKG) system is the second fundamental blood pressure regulator. Whether both systems influence each other is not well-studied. It has been shown that nitric oxide (NO) supports renin recruitment via activation of soluble guanylate cyclase (sGC) and subsequent generation of cGMP. Whether this leads to an ensuing activation of PKGs in this context is not known. PKGI alpha, as well as PKGII, is expressed in renin-producing cells. Hence, we analyzed whether these enzymes play a role regarding renin synthesis, secretion, or recruitment. We generated renin-cell-specific PKGI-knockout mice and either stimulated or inhibited the renin system in these mice by salt diets. To exclude the possibility that one kinase isoform can compensate the lack of the other, we also studied double-knockout animals with a conditional knockout of PKGI in juxtaglomerular cells (JG cells) and a ubiquitous knockout of PKGII. We analyzed blood pressure, renin mRNA and renal renin protein content as well as plasma renin concentration. Furthermore, we stimulated the cGMP system in these mice using BAY 41-8543, an sGC stimulator, and examined renin regulation either after acute administration or after 7 days (application once daily). We did not reveal any striking differences regarding long-term renin regulation in the studied mouse models. Yet, when we studied the acute effect of BAY 41-8543 on renin secretion in isolated perfused kidneys as well as in living animals, we found that the administration of the substance led to a significant increase in plasma renin concentration in control animals. This effect was completely abolished in double-knockout animals. However, after 7 days of once daily application, we did not detect a persistent increase in renin mRNA or protein in any studied genotype. Therefore, we conclude that in mice, cGMP and PKG are involved in the acute regulation of renin release but have no influence on long-term renin adjustment

Urinary renin in patients and mice with diabetic kidney disease

In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary renin was evaluated in samples from patients with longstanding type I diabetes mellitus and mice with streptozotocin-induced diabetes mellitus. Renin-reporter mouse model (Ren1d-Cre;mT/ mG) was made diabetic with streptozotocin to examine whether the distribution of cells of the renin lineage was altered in a chronic diabetic environment. Active renin was increased in urine samples from patients with DKD (n=36), compared with those without DKD (n=38; 3.2 versus 1.3 pg/mg creatinine; P<0.001). In mice with streptozotocin-induced diabetes mellitus, urine renin was also increased compared with nondiabetic controls. By immunohistochemistry, in mice with streptozotocin-induced diabetes mellitus, juxtaglomerular apparatus and proximal tubular renin staining were reduced, whereas collecting tubule staining, by contrast, was increased. To examine the role of filtration and tubular reabsorption on urinary renin, mice were either infused with either mouse or human recombinant renin and lysine (a blocker of proximal tubular protein reabsorption). Infusion of either form of renin together with lysine markedly increased urinary renin such that it was no longer different between nondiabetic and diabetic mice. Megalin mRNA was reduced in the kidney cortex of streptozotocin-treated mice (0.70±0.09 versus 1.01±0.04 in controls, P=0.01) consistent with impaired tubular reabsorption. In Ren1d-Cre;mT/mG with streptozotocin-induced diabetes mellitus, the distribution of renin lineage cells within the kidney was similar to nondiabetic renin-reporter mice. No evidence for migration of cells of renin linage to the collecting duct in diabetic mice could be found. Renin mRNA in microdissected collecting ducts from streptozotocin-treated mice, moreover, was not significantly different than in controls, whereas in kidney cortex, largely reflecting juxtaglomerular apparatus renin, it was significantly reduced. In conclusion, in urine from patients with type 1 diabetes mellitus and DKD and from mice with streptozotocin-induced diabetes mellitus, renin is elevated. This cannot be attributed to production from cells of the renin lineage migrating to the collecting duct in a chronic hyperglycemic environment. Rather, the elevated levels of urinary renin found in DKD are best attributed to altered glomerular filteration and impaired proximal tubular reabsorption.Fil: Tang, Jeannette. Northwestern University; Estados UnidosFil: Wysocki, Jan. Northwestern University; Estados UnidosFil: Ye, Minghao. Northwestern University; Estados UnidosFil: Garramuño, Patricia. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Rein, Johannes. Northwestern University; Estados UnidosFil: Shirazi, Mina. Northwestern University; Estados UnidosFil: Bader, Michael. Charité Universitätsmedizin; AlemaniaFil: Gomez, Roberto Ariel. University of Virginia; Estados UnidosFil: Sequeira Lopez, Maria Luisa S.. University of Virginia; Estados UnidosFil: Afkarian, Maryam. University of California at Davis; Estados UnidosFil: Batlle, Daniel. Northwestern University; Estados Unido

Comparative Studies of Renin-Null Zebrafish and Mice Provide New Functional Insights

Background: The renin-angiotensin system is highly conserved across vertebrates, including zebrafish, which possess orthologous genes coding for renin-angiotensin system proteins, and specialized mural cells of the kidney arterioles, capable of synthesising and secreting renin. Methods: We generated zebrafish with CRISPR-Cas9-targeted knockout of renin ( ren −/− ) to investigate renin function in a low blood pressure environment. We used single-cell (10×) RNA sequencing analysis to compare the transcriptome profiles of renin lineage cells from mesonephric kidneys of ren −/− with ren +/+ zebrafish and with the metanephric kidneys of Ren1 c −/− and Ren1 c +/+ mice. Results: The ren −/− larvae exhibited delays in larval growth, glomerular fusion and appearance of a swim bladder, but were viable and withstood low salinity during early larval stages. Optogenetic ablation of renin-expressing cells, located at the anterior mesenteric artery of 3-day-old larvae, caused a loss of tone, due to diminished contractility. The ren −/− mesonephric kidney exhibited vacuolated cells in the proximal tubule, which were also observed in Ren1 c −/− mouse kidney. Fluorescent reporters for renin and smooth muscle actin ( Tg(ren:LifeAct-RFP; acta2:EGFP )), revealed a dramatic recruitment of renin lineage cells along the renal vasculature of adult ren −/− fish, suggesting a continued requirement for renin, in the absence of detectable angiotensin metabolites, as seen in the Ren1 YFP Ren1 c −/− mouse. Both phenotypes were rescued by alleles lacking the potential for glycosylation at exon 2, suggesting that glycosylation is not essential for normal physiological function. Conclusions: Phenotypic similarities and transcriptional variations between mouse and zebrafish renin knockouts suggests evolution of renin cell function with terrestrial survival

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Leukemia development initiated by deletion of RBP-J: mouse strain, deletion efficiency and cell of origin

Conditional deletion of RBP-J, the major transcriptional effector of Notch signaling, specifically within renin-expressing cells leads to the development of B-cell leukemia. However, the influence of contributing factors such as mouse strain, cell of origin and Cre recombinase copy number are unknown. In this study, we compared RBP-J deletion efficiency using one versus two copies of Cre recombinase. Further, we compared the incidence and timing of leukemia development in two unique strains of mice, C57BL/6 and 129/SV, as well as at different B-cell developmental stages. We found that animals expressing two copies of Cre recombinase developed B-cell leukemia at an earlier age and with more fulminant disease, compared with control animals and animals expressing one copy of Cre recombinase. In addition, we found a difference in leukemia incidence between C57BL/6 and 129/SV mouse strains. Whereas deletion of RBP-J in renin-expressing cells of C57BL/6 mice leads to the development of B-cell leukemia, 129/SV mice develop dermatitis with a reactive, myeloproliferative phenotype. The difference in phenotypes is explained, in part, by the differential expression of extra-renal renin; C57BL/6 mice have more renin-expressing cells within hematopoietic tissues. Finally, we found that deletion of RBP-J in Mb1- or CD19-expressing B lymphocytes does not result in leukemia development. Together, these studies establish that renin progenitors are vulnerable cells for neoplastic transformation and emphasize the importance of genetic background on the development of inflammatory and malignant conditions. This article has an associated First Person interview with the first author of the paper