Hormonal systems in renal and cardiovascular diseases: from cell biology to new physiological paradigms with advances for therapeutics

• Grant number: 17/17027-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2020
• End date: September 30, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Dulce Elena Casarini
• Grantee: Dulce Elena Casarini
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Alexis A Gonzalez ; Bruno Moreira Silva ; Elisa Mieko Suemitsu Higa ; Fernanda Aparecida Ronchi ; Fernanda Klein Marcondes ; Helio Tedesco Silva Junior ; José Geraldo Mill ; Juliana Dinéia Perez Brandão ; Larissa Miranda Pereira ; Leuridan Cavalcante Torres ; Lilian Caroline Gonçalves de Oliveira ; Lucienne da Silva Lara Morcillo ; Manuela Sofia Rodrigues Morato ; Maria Claudia Costa Irigoyen ; Mariane Bertagnolli ; Mário Luís Ribeiro Cesaretti ; Minolfa C. Prieto ; Mirian Aparecida Boim ; Tatiana de Sousa da Cunha Uchiyama ; Zaira Palomino Jara
• Associated research grant(s): 22/08494-1 - Multi-user Equipament approved in grant 2017/17027-0: Microplate Reader Tecan Infinite 200 Pro, AP.EMU
• Associated scholarship(s): 22/12176-5 - Cerebrovascular Regulation in Patients with Pulmonary Arterial Hypertension who Present with Symptomatic Orthostatic Hypotension, BP.PD; 23/13765-7 - Molecular mechanisms of RAS components under the influence of inhibitors and hormones, BP.TT; 23/09271-9 - Effect of chronic stress on metabolic and hormonal markers in rats, BP.IC; + associated scholarships 22/07245-8 - CHRONIC STRESS AND HIPPOCAMPAL NEUROGENESIS: ROLE OF PROBIOTICS AND LIPIDOMIC AND HORMONAL IMPLICATIONS, BP.DR; 22/08215-5 - Evaluation of a low-cost insulin infusion pump prototype through in vitro and in vivo assays, BP.IC; 22/02452-5 - Placental vascularization disorders associated with renin angiotensin changes in pregnant women with COVID-19, BP.PD; 21/05331-1 - Role of probiotics Lactobacillus reuteri and Lactobacillus rhamnosus on the inflammatory profile and renin angiotensin system in an experimental model of chronic stress, BP.DR; 21/11209-4 - Contribution of venous return to increased ventilation pulmonary during the beginning of physical exercise, BP.IC; 21/06091-4 - Outline the signaling network triggered by treatment with Captopril and highlight the effects that are not explained only in terms of blocking the catalytic activity of ACE, BP.PD; 21/06090-8 - Role of endurance training on chronic stress-induced cardiac hypertrophy: involvement of the renin angiotensin system, JNK and p38 MAPK signaling pathways, BP.PD - associated scholarships

Abstract

Cardiovascular and renal diseases are among the main "non-contagious pandemics" because they are responsible for exponential increase in morbidity and early mortality around the world. Common risk factors for cardiovascular and kidney diseases include: hypertension, diabetes, obesity and stress. Interestingly the participation of the renin angiotensin aldosterone system (RAS) has been evidenced in the pathophysiology of these various diseases, being a common point of modulation and/ or deregulation. RAS has extensive complexity, since it comprises several interconnecting and counterbalancing axes, its signaling profile permeates from autocrine and paracrine communication to endocrine and RAS interacts with several other hormonal systems essential to homeostasis, such as the kallikrein kinins system (KKS), prostaglandins and corticosteroids. Due to its wide complexity and importance in the pathophysiology of several diseases that converge on the main global causes of death from non-contagious diseases, RAS is a fertile field for research, especially in translating the results into clinical practice and public health policies. Based on the above, this thematic project aims to: evaluate the molecular mechanisms of cellular communication and the interactions of RAS components within and between systems against various treatments with RAS inhibitors and hormones; describe the modulation of RAS in response to potential new drugs, contemplating to elucidate the possible modulated mechanisms of action that may result in the desired pharmacological effect; to verify the role of the interaction of RAS with the KKS and with pro-renin and purinergic P2X7 receptors in the pathophysiology of cardiovascular, renal and obesity diseases; to evaluate how the RAS components are modulated in different pathophysiological states in order to identify prognostic and diagnostic biomarkers; and to investigate the response of RAS and its physiological effects in face of stressors and physical exercise. To this end, this thematic project will involve 19 challenges that are divided into three different research axes, the first axis corresponds to the study of the molecular mechanisms and interaction of RAS, the second axis is focused on the investigation of new drugs and biomarkers and the third has based on the investigation of RAS response to stress and exercise. The proposed challenges include basic and applied research, experimental models in cells and animals, and also population studies. Thus, the implementation of this thematic project will contribute to fill gaps in knowledge about the molecular and physiological mechanisms involving RAS and that are related to the development and progression of cardiovascular and renal diseases. Among the gains arising from the implementation of this project we can list: the identification of new therapeutic targets, the discovery of potential new drugs and biomarkers for diagnosis and prognosis, as well as a better understanding of the benefits of protective and prophylactic methods. Thus, consolidating knowledge for the development of new therapeutic approaches and public health policies, which benefit society as a whole. In addition to the contribution in the scientific and social sphere, it is important to highlight the contribution of this project in the formation of new researchers and scientific technical personnel, who will perpetuate the development and progress of national science. (AU)

Scientific publications

(11)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GASPAR, ANA R.; ANDRADE, BEATRIZ; MOSCA, SARA; FERREIRA-DUARTE, MARIANA; TEIXEIRA, ANA; COSME, DINA; ALBINO-TEIXEIRA, ANTONIO; RONCHI, FERNANDA A.; LEITE, ANA P.; CASARINI, DULCE E.; et al. Association between blood pressure and angiotensin-converting enzymes activity in prepubertal children*. Journal of Hypertension, v. 41, n. 4, p. 9-pg., 2023-04-01. (17/17027-0)

VISNIAUSKAS, BRUNA; REVERTE, VIRGINIA; ABSHIRE, CALEB M.; OGOLA, BENARD O.; ROSALES, CARLA B.; GALEAS-PENA, MICHELLE; SURE, VENKATA N.; SAKAMURI, SIVA S. V. P.; HARRIS, NICHOLAS R.; KILANOWSKI-DOROH, ISABELLA; et al. High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 324, n. 6, p. 14-pg., 2023-06-01. (17/17027-0)

FERREIRA-DUARTE, MARIANA; OLIVEIRA, LILIAN CAROLINE GONCALVES; QUINTAS, CLARA; DIAS-PEREIRA, PATRICIA; SOUSA, TERESA; MAGRO, FERNANDO; CASARINI, DULCE ELENA; DUARTE-ARAUJO, MARGARIDA; MORATO, MANUELA. Angiotensin-converting enzymes 1 and 2 in the feces: presence and catalytic activity in the rat 2,4,6-trinitrobenzene sulfonic acid-induced model of colitis. JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, v. 39, n. 9, p. 10-pg., 2024-07-05. (17/17027-0)

CRUZ, NAYARA AZINHEIRA NOBREGA; OLIVEIRA, LILIAN CAROLINE GONCALVES DE; SILVA JUNIOR, HELIO TEDESCO; PESTANA, JOSE OSMAR MEDINA; CASARINI, DULCE ELENA. Angiotensin-Converting Enzyme 2 in the Pathogenesis of Renal Abnormalities Observed in COVID-19 Patients. FRONTIERS IN PHYSIOLOGY, v. 12, AUG 23 2021. (17/17027-0, 18/16653-7, 18/23953-7)

GONSALEZ, SABRINA R.; GOMES, DAYENE S.; DE SOUZA, ALESSANDRO M.; FERRAO, FERNANDA M.; VALLOTTON, ZOE; GOGULAMUDI, VENKATESWARA R.; LOWE, JENNIFER; CASARINI, DULCE E.; PRIETO, MINOLFA C.; LARA, LUCIENNE S.. The Triad Na+ Activated Na+ Channel (Nax)-Salt Inducible KINASE (SIK) and (Na+ + K+)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 9, p. 25-pg., 2023-04-26. (17/17027-0)

RICELLI, BRUNA; ARAGAO, DANIELLE; PEREIRA, LARISSA; CASARINI, DULCE. Biochemical and Kinetic Characterization of Angiotensin I Converting Enzymes (ACE) with Site-Directed Amino Acid Changes: Interactions with Its Specific Inhibitors. FASEB JOURNAL, v. 35, p. 2-pg., 2021-05-01. (17/17027-0)

LARA, LUCIENNE S.; GONZALEZ, ALEXIS A.; HENRRIKUS, MATTHEW A.; PRIETO, MINOLFA C.. The Role of (Pro)Renin Receptor in the Metabolic Syndrome. CURRENT HYPERTENSION REVIEWS, v. 18, n. 2, p. 10-pg., 2022-01-01. (17/17027-0)

LARENAS, PAULINA E.; CARDENAS, PILAR; AGUIRRE-DELGADILLO, MONSERRAT; MORIS, CARLOS; CASARINI, DULCE E.; VALLOTTON, ZOE; PRIETO, MINOLFA C.; GONZALEZ, ALEXIS A.. GLUT1 and prorenin receptor mediate differential regulation of TGF-β and CTGF in renal inner medullary collecting duct cells during high glucose conditions. Biological Research, v. 57, n. 1, p. 14-pg., 2024-11-07. (17/17027-0)

CRUZ, NAYARA AZINHEIRA NOBREGA; DE OLIVEIRA, LILIAN CAROLINE GONCALVES; FERNANDES, FERNANDA BARRINHA; ZANIQUELI, DIVANEI DOS ANJOS; OLIOSA, POLYANA ROMANO; MILL, JOSE GERALDO; CASARINI, DULCE ELENA. An Output-Space Based Branch-and-Bound Algorithm for Sum-of-Linear-Ratios Problem. HYPERTENSION RESEARCH, v. 46, n. 6, p. 12-pg., 2023-03-24. (18/16653-7, 17/17027-0)

DOS SANTOS, LILIAN; RIBEIRO, LYS ANGELA FAVARONI MENDES SALGADO; GOMES, ANDREIA CRISTINA FEBBA; CRUZ, NAYARA AZINHEIRA NOBREGA; DE OLIVEIRA, LILIAN CAROLINE GONSALVES; CENEDEZE, MARCOS ANTONIO; SILVA JUNIOR, HELIO TEDESCO; PESTANA, JOSE OSMAR MEDINA; CASARINI, DULCE ELENA. ACE and ACE2 activities and polymorphisms assessment: A populational study from Ipaussu (SP, Brazil) during the COVID-19 pandemic. Life Sciences, v. 358, p. 11-pg., 2024-10-23. (17/17027-0)

CARDENAS, PILAR; NUNEZ-ALLIMANT, CAMILA; SILVA, KATHERIN; CID-SALINAS, CATALINA; LEON, ALLISON C.; VALLOTTON, ZOE; LORCA, RAMON A.; DE OLIVEIRA, LILIAN CAROLINE GONCALVES; CASARINI, DULCE E.; CESPEDES, CARLOS; et al. OXGR1-Dependent (Pro)Renin Receptor Upregulation in Collecting Ducts of the Clipped Kidney Contributes to Na⁺ Balance in Goldblatt Hypertensive Mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 18, p. 19-pg., 2024-09-01. (17/17027-0)