Autophagy and cellular senescence on voiding dysfunction and benign prostatic hyperplasia in obesity

• Grant number: 19/09912-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: July 01, 2020
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Fabiano Beraldi Calmasini
• Grantee: Fabiano Beraldi Calmasini
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 23/05123-5 - Autophagy and Cellular Senescence in Urinary Dysfunction in Obesity, BP.MS; 20/06254-8 - Autophagy and cell senescence in obesity-induced benign prostatic hyperplasia, BP.JP

Abstract

The worldwide incidence of obesity has increased dramatically in the past 25 years, and today is considered one of the most major public health problems. Clinical studies indicate a strong correlation between obesity and genitourinary tract diseases, such as voiding dysfunction and benign prostatic hyperplasia (BPH). Experimental studies demonstrated impaired voiding cycle and increased cell proliferation, resulting in prostate enlargement, in high-fat diet (HFD)-induced obese animals. Furthermore, obesity led to prostate and detrusor smooth muscle hypercontractility, which contributes to BPH and voiding dysfunction, respectively. However, the pathophysiology of the bladder and prostate impairments in obesity remains poorly understood and the available clinical treatments show low effectiveness. Recent and independent studies have been shown the reduction in autophagy process and the increase in oxidative stress levels and senescent cells accumulation in the genesis/maintenance of metabolic and tissue impairments, secondary to obesity. Nonetheless, little is known about the role of these alterations in the obesity-associated genitourinary tract dysfunctions. Preliminary studies evaluated the effects of obesity in the prostatic and bladder function. We demonstrated that the ventral prostatic weight, a parameter increased in BPH patients, was increased in obese mice. We also found ventral prostate and bladder smooth muscle hypercontractility induced by phenylephrine and carbacol in obese group, respectively. Obesity increased by 56% and 31% the basal levels of reactive oxygen species (ROS) in ventral prostatic and bladder tissues of obese group compared with control animals. In vivo protocols using cistometry assay revealed obesity-induced voiding impairments, characterized mainly by increase in voiding frequency in obese group. Our results also indicated increase in ²-galactosidase positive cells (a marker for cellular senescence) and reduction in LC3 protein expression (protein involved in autophagy process) in ventral prostate of obese group. Therefore, we hypothesized that BPH and voiding dysfunction, secondary to obesity, have in common a reduction in local autophagy process with consequent unbalance in tissue oxidative state. The increased levels of ROS levels lead to augmented senescent cells accumulation, which are responsible for inflammatory interleukins and growth factor release. The senescent-associated secretory phenotype (SASP) of senescent cells would exert a key role on smooth muscle hypercontractility and tissue growth and/or remodeling seen in obesity-associated BPH and LUTS. Thus, the aim of the present project is to evaluate functional, structural and molecular alterations by high-fat diet-induced obesity in ventral prostate and bladder from obese mice, focusing in the link between obesity, reduced autophagy process and senescent cells accumulation in the genesis of BPH and LUTS. We also intended to evaluate the effects of chronic treatment with drugs that modulate the autophagy process and senescent cells accumulation, aiming to restore the voiding and prostatic patterns in the obese group. If our hypothesis is right, the pathways involved in autophagy activation and consequently senescent cells reduction will represent new therapeutic target for the development of new drugs to treat obesity-related voiding and prostatic impairments. (AU)

Scientific publications

(4)

(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)

CALMASINI, F. B.; SILVA, F. H.; ALEXANDRE, E. C.; ANTUNES, E.. Efficacy of resveratrol in male urogenital tract dysfunctions: an evaluation of pre-clinical data. NUTRITION RESEARCH REVIEWS, v. N/A, p. 12-pg., 2021-11-15. (19/09912-9, 20/06254-8)

ALBERTO FERNANDO OLIVEIRA JUSTO; RITA DE CÁSSIA COLLAÇO; ANNA LIGIA OENNING SOARES; CAROLINE MARQUES CALOI; CAMILA STEFANI ESTANCIAL; GUILHERME LEMOS; FABIO HENRIQUE DA SILVA; EDUARDO COSTA ALEXANDRE; FABIANO BERALDI CALMASINI. Hospitalization and mortality rates of malignant prostatic neoplasms in Brazil: A cross-sectional study from 2008 to 2018. Brazilian Journal of Pharmaceutical Sciences, v. 60, 2024-02-26. (19/09912-9, 23/05123-5, 21/14171-8)

TABATHA DANIELLE DA SILVA LOPES; RENAN BAZUCO FRITOLI; FABIO HENRIQUE DA SILVA; FABIANO BERALDI CALMASINI. Aging-associated prostate smooth muscle hypercontractility in rats. Brazilian Journal of Pharmaceutical Sciences, v. 58, 2023-01-09. (14/02195-6, 19/09912-9)

LEMOS, GUILHERME; FERNANDES, CICERA MADRI ALVES DE SOUZA; WATANABE, INGRID KAZUE MIZUNO; DELBIN, MARIA ANDREIA; SILVA, FABIO HENRIQUE; CALMASINI, FABIANO BERALDI. Trehalose induces bladder smooth muscle hypercontractility in mice: involvement of oxidative stress and cellular senescence. FRONTIERS IN PHYSIOLOGY, v. 16, p. 9-pg., 2025-04-04. (19/09912-9, 23/05123-5)