Autophagy and Cellular Senescence in Urinary Dysfunction in Obesity

• Grant number: 23/05123-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2023
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Fabiano Beraldi Calmasini
• Grantee: Guilherme Lemos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/09912-9 - Autophagy and cellular senescence on voiding dysfunction and benign prostatic hyperplasia in obesity, AP.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 indicatea strong correlation between obesity and genitourinary tract diseases, such as voidingdysfunction and benign prostatic hyperplasia (BPH). Experimental studies demonstratedimpaired voiding cycle and increased cell proliferation, resulting in prostate enlargement, inhigh-fat diet (HFD)-induced obese animals. Furthermore, obesity led to prostate and detrusorsmooth muscle hypercontractility, which contributes to BPH and voiding dysfunction,respectively. However, the pathophysiology of the bladder and prostate impairments in obesityremains poorly understood and the available clinical treatments show low effectiveness. Recentand independent studies have been shown the reduction in autophagy process and the increasein oxidative stress levels and senescent cells accumulation in the genesis/maintenance ofmetabolic and tissue impairments, secondary to obesity. Nonetheless, little is known about therole of these alterations in the obesity-associated genitourinary tract dysfunctions. Preliminarystudies evaluated the effects of obesity in the bladder function. We demonstrated that the ventralprostatic weight, a parameter increased in BPH patients and closely related with voidingdysfunctions, was increased in obese mice. We also found bladder smooth musclehypercontractility induced by carbacol in obese group. Obesity increased by 31% the basallevels of reactive oxygen species (ROS) in bladder tissues of obese group compared withcontrol animals. In vivo protocols using cistometry assay revealed obesity-induced voidingimpairments, characterized mainly by increase in voiding frequency in obese group. Therefore,we hypothesized that voiding dysfunction, secondary to obesity, has in common a reduction inlocal autophagy process with consequent unbalance in tissue oxidative state. The increasedlevels of ROS levels lead to augmented senescent cells accumulation, which are responsible forinflammatory interleukins and growth factor release. The senescent-associated secretoryphenotype (SASP) of senescent cells would exert a key role on smooth musclehypercontractility and tissue growth and/or remodeling seen in obesity-associated lower urinarytract symptoms (LUTS). Thus, the aim of the present project is to evaluate functional, structuraland molecular alterations by high-fat diet-induced obesity in bladder from obese mice, focusingon the link between obesity, reduced autophagy process and senescent cells accumulation in thegenesis of LUTS. We also intended to evaluate the effects of chronic treatment with drugs thatmodulate the autophagy process and senescent cells accumulation, aiming to restore the voidingpatterns in the obese group. If our hypothesis is right, the pathways involved in autophagyactivation and consequently senescent cells reduction will represent new therapeutic target forthe development of new drugs to treat obesity-related voiding impairments.

Scientific publications

(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)

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. (21/14171-8, 19/09912-9, 23/05123-5)