by Keyword: Renin

Liu, M, Zhang, C, Gong, XM, Zhang, T, Lian, MM, Chew, EGY, Cardilla, A, Suzuki, K, Wang, HM, Yuan, Y, Li, Y, Naik, MY, Wang, YX, Zhou, BR, Soon, WZ, Aizawa, E, Li, P, Low, JH, Tandiono, M, Montagud, E, Moya-Rull, D, Esteban, CR, Luque, Y, Fang, ML, Khor, CC, Montserrat, N, Campistol, JM, Belmonte, JCI, Foo, JN, Xia, Y, (2024). Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo Cell Stem Cell 31, 52-70.e8

Human pluripotent stem cell -derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single -cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA -approved drug, effectively attenuated cyst formation in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

JTD Keywords: Adenylate kinase, Adult, Animal cell, Animal experiment, Animal model, Animal tissue, Article, Autophagosome, Autophagy, Autophagy (cellular), Autosomal-dominant, Calcium homeostasis, Cilia, Cilium, Cohort analysis, Controlled study, Cyclic amp, Disease, Dominant polycystic kidney, Enzyme linked immunosorbent assay, Epithelium, Exon, Expression, Female, Food and drug administration, Framework, Generation, Growth, Hepatitis a virus cellular receptor 1, Human, Human cell, Humans, Immunohistochemistry, In vitro study, In vivo study, Kidney, Kidney organoid, Kidney polycystic disease, Male, Minoxidil, Mouse, Mutations, Nonhuman, Organoid, Organoids, Platelet derived growth factor beta receptor, Pluripotent stem-cells, Polycystic kidney diseases, Protein kinase lkb1, Renin, Sequestosome 1, Single cell analysis, Single cell rna seq, Small nuclear rna, Tunel assay, Upregulation, Western blotting, Whole exome sequencing

Ortiz, C, Klein, S, Reul, WH, Magdaleno, F, Gröschl, S, Dietrich, P, Schierwagen, R, Uschner, FE, Torres, S, Hieber, C, Meier, C, Kraus, N, Tyc, O, Brol, M, Zeuzem, S, Welsch, C, Poglitsch, M, Hellerbrand, C, Alfonso-Prieto, M, Mira, F, Keller, UAD, Tetzner, A, Moore, A, Walther, T, Trebicka, J, (2023). Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1 Cell Reports 42, 112059

Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

JTD Keywords: activation, cirrhosis, cirrhotic rats, cp: cell biology, expression, hepatic stellate cell, identification, inhibition, mechanisms, modulation, neprilysin, neuropeptide y, neuropeptide y receptor 1, portal hypertension, portal-hypertension, web server, Renin-angiotensin system

Gawish, R, Starkl, P, Pimenov, L, Hladik, A, Lakovits, K, Oberndorfer, F, Cronin, SJF, Ohradanova-Repic, A, Wirnsberger, G, Agerer, B, Endler, L, Capraz, T, Perthold, JW, Cikes, D, Koglgruber, R, Hagelkruys, A, Montserrat, N, Mirazimi, A, Boon, L, Stockinger, H, Bergthaler, A, Oostenbrink, C, Penninger, JM, Knapp, S, (2022). ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFNy-driven immunopathology Elife 11, e74623

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al.

JTD Keywords: covid-19 mouse model, covid-19 therapy, cytokine storm, immunology, inflammation, mavie16, mouse, mouse-adapted sars-cov-2, program, recombinant soluble ace2, tmprss2, Adaptive immunity, Angiotensin converting enzyme 2, Angiotensin-converting enzyme 2, Animal, Animal cell, Animal experiment, Animal model, Animal tissue, Animals, Apoptosis, Article, Bagg albino mouse, Breathing rate, Bronchoalveolar lavage fluid, C57bl mouse, Cell composition, Cell infiltration, Controlled study, Coronavirus disease 2019, Coronavirus spike glycoprotein, Covid-19, Cytokeratin 18, Cytokine production, Dipeptidyl carboxypeptidase, Disease model, Disease models, animal, Disease severity, Drosophila-melanogaster, Enzyme linked immunosorbent assay, Expression vector, Flow cytometry, Gamma interferon, Gene editing, Gene expression, Gene mutation, Genetic engineering, Genetics, Glycosylation, High mobility group b1 protein, Histology, Histopathology, Immune response, Immunocompetent cell, Immunology, Immunopathology, Interferon-gamma, Interleukin 2, Metabolism, Mice, inbred balb c, Mice, inbred c57bl, Mouse-adapted sars-cov-2, Myeloperoxidase, Neuropilin 1, Nonhuman, Nucleocapsid protein, Pathogenicity, Peptidyl-dipeptidase a, Pyroptosis, Recombinant soluble ace2, Renin angiotensin aldosterone system, Rna extraction, Rna isolation, Sars-cov-2, Severe acute respiratory syndrome coronavirus 2, Spike glycoprotein, coronavirus, T lymphocyte activation, Trabecular meshwork, Tumor necrosis factor, Virology, Virus load, Virus replication, Virus transmission, Virus virulence