Investigating Cisplatin Renal Tubular Secretion Mechanisms via Human 3D Kidney Organoids

• Grant number: 24/22400-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: April 01, 2025
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Ronaldo de Carvalho Araújo
• Grantee: Gabriel Rufino Estrela
• Supervisor: Giuliano Ciarimboli
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: University of Munster, Germany
• Associated to the scholarship: 20/15895-7 - Balance between kinin B1 and B2 receptors in the development of tubulointerstitial fibrosis, BP.PD

Abstract

Cisplatin is a chemotherapeutic agent applied in treatment protocols of numerous cancer entities. However, cisplatin and other platinum agents can cause severe adverse side effects, such as nephro-, oto- and peripheral neurotoxicity. Mechanisms of platinum- induced nephrotoxicity have been analyzed in rodents and human cell lines revealing that cisplatin is accumulated intracellularly in proximal tubular cells due to transport via basolateral organic cation transporters. As concentrative transporters, these organic cation transporters mediate the intracellular accumulation of cisplatin in proximal tubular cells along the electrochemical gradient, which by far exceeds the extracellular concentrations. Despite attempts to attenuate the nephrotoxic potential, currently there are no specific options for prevention or treatment. Kidney organoids differentiated form human induced pluripotent stem cells offer the unique possibility to characterize cisplatin-induced nephrotoxicity in a three-dimensional human model. We hypothesize that the organic cation transporter 2 (OCT2) plays a central role in the intracellular accumulation of cisplatin in humans. We propose that targeting and reducing cation transport via OCT2 could prevent cisplatin uptake and subsequent damage to proximal tubular cells, while leaving its excretion at the luminal membrane unaffected. The primary goal of this project is to gain a deeper understanding of the pathophysiology of cisplatin-induced kidney injury using a human disease model. By utilizing 3D kidney tissue, which is a novel approach and more closely mimic the complexity and behavior of real tissues and organs, we aim to elucidate the molecular mechanisms underlying cisplatin accumulation and its toxic effects in vitro. Additionally, we seek to determine whether pharmacological inhibition of OCT2 in the proximal tubule offers a viable approach for both prevention and treatment. The findings from this study will contribute to a clearer understanding of cisplatin-induced nephrotoxicity and provide a foundation for future research and therapeutic development. This model of cisplatin- induced nephrotoxicity can provide a valuable framework for exploring genetic and pharmacological therapies, as well as serving as a platform to investigate other forms of kidney damage.