Role of p38MAPK and ERK1/2 in the modulation of MMP10 in proximal tubule cells in an experimental model of cisplatin.

• Grant number: 25/01468-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Maria Oliveira de Souza
• Grantee: Thayná Vitoria Ribeiro da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cisplatin is an antineoplastic molecule extensively used in the treatment of breast, cervical, esophageal, bladder, lung and testicular cancers, and a potent nephrotoxic agent responsible for the induction of acute kidney injury (AKI), with a focus on tubular injury. To date, little is known about the effect of cisplatin on the cellular mechanisms responsible for tubular injuries. On the other hand, studies in diabetes models report the renoprotective and/or renal injury role of matrix metalloproteinase 10 (MMP10). Thus, our hypothesis is that in the cisplatin-induced acute kidney injury model, proximal tubule cell injury and repair may be associated with the action of p38MAPK (apoptotic pathway), ERK1/2 (proliferative pathway) and MMP10. The aim of this study is to identify the mechanisms responsible for proximal tubule cell injury in the in vivo and in vitro cisplatin model in the acute phase of renal disease, investigating the involvement of p38MAPK, ERK1/2 and MMP10 in the apoptotic and proliferative responses during tubular epithelial repair. In the in vivo study, renal tissue from 8-week-old male BALBc mice will be used. The animals were organized into control groups (received injections of 0.9% NaCl saline solution) or treated with cisplatin (received injections of a single dose of 20mg/kg diluted in 0.9% NaCl saline solution). The animals were euthanized on the 4th day after cisplatin injection. For the in vitro study, TKPTS cells (from the renal proximal tubule) will be treated with 100 ¿M cisplatin and/or SB203580 (p38MAPK inhibitor, 1¿M) and PD98059 (MEK/ERK pathway inhibitor, 1 ¿M). The methodologies provided include Western blotting, immunohistochemistry and immunofluorescence to evaluate protein expression and distribution. Statistical analysis will be performed by one-way or two-way ANOVA and Bonferroni's post-test and, when necessary, the t-test. p<0.05 will be considered significant in comparison to the control or treated. The results will be presented as mean value ± standard deviation.