Evaluation of Inflammatory Effect on Renal Drug Transporter Expression Using Human Kidney Biopsies and 3D-RPTECs

Includes a Live Web Event on 09/28/2026 at 5:00 PM (EDT)

Abstract: In patients with renal impairment, tubular secretion of drugs via drug transporters is reduced. As a possible mechanism, the chronic inflammatory state associated with renal injury may affect the expression and activity of drug transporters. However, the relationship between inflammatory status and drug transporter expression have not been clarified using patient samples. In this study, we analyzed the expression levels of drug transporters in human kidney specimens and examined the effects of inflammatory cytokines on the expression and activity of renal drug transporters, organic anion transporter (OAT) 1 and 3, using three-dimensionally cultured human proximal tubular epithelial cells (3D-RPTEC) [1,2]. Proteomic analysis of non-tumor portion specimens of kidneys removed from patients with renal tumors revealed 93 transporters including OAT1. Enrichment analysis of proteins negatively correlated with OAT1 and OAT3 expression in human kidney using Metascape revealed GO terms related to inflammation. To characterize the direct effects of inflammatory cytokines on RPTECs, IL-1β and TNFα were exposed to 3D-RPTECs. As a result, mRNA expression of OAT1 and OAT3 was decreased and the uptake activity of the OAT1 substrate [3H] PAH was reduced. The decrease in mRNA expression due to inflammatory cytokine exposure was suppressed by the addition of the NF-κB inhibitor benzoxathiole. In conclusion, our studies revealed that inflammatory cytokines negatively regulate the expression of renal drug transporters OAT1 and OAT3.

Learning Objectives:

- What is the role of renal drug transporters?
- How does renal impairment and/or inflammation affect renal function (especially transporter function)
- Familiarization with methods and tools that can be used to study renal drug handling

Target Audience: DMPK scientists with particular interest in renal drug transport and the effect of disease / inflammation on kidney function.

Educational Needs Statement: Knowledge gaps continue to exist regarding the impact of renal disease on drug transport in proximal tubular cells

Hiroshi Arakawa, PhD

Professor

Nagoya City University

Academic Career 2013 Kanazawa University, Japan Ph.D. in Pharmacokinetics
2009 Tokyo University of Science, Japan M.S. in Pharmacokinetics
2007 Tokyo University of Science B.S. in Pharmacokinetics

Professional Experience 2025–present Full Professor Graduate School of Pharmaceutical Sciences, Nagoya City University
2021–2025 Associate Professor Faculty of Pharmacy, Kanazawa University, Japan
2016–2021 Assistant Professor Faculty of Pharmacy, Kanazawa University, Japan
2013–2016 Assistant Professor Faculty of Pharmacy, Takasaki University of Health and Welfare, Japan

Kunal Taskar (Moderator)

Director, Global Head of PBPK Modelling

GSK

Kunal Taskar, Ph.D., is currently working as Director, Global Head of PBPK Modelling at GSK. Kunal completed his doctorate more than a decade ago and postdoctoral research at Texas Tech University Health Sciences department, USA, in Quentin Smith’s lab with research focused on Neuropharmacokinetics and role of transporters in drug delivery across the blood-brain barrier (BBB).

Kunal’s experience and research focus include: PBPK modeling of small/large molecules and new modalities for PK and dose predictions, drug-drug interaction predictions and mechanistic understanding of the clinically occurring drug–drug interactions; and application of PBPK modeling in special populations including pediatrics, pregnancy, and organ impairment. His expertise also includes transporter mediated drug delivery and intracellular drug concentrations, especially the role of uptake and efflux transporters in drug pharmacokinetics-pharmacodynamics in disease and toxicology; novel transporters and role in drug disposition and use of endogenous probes and modeling for drug mediated transporter modulations.

Kunal is a member of American Society of Clinical Pharmacology and Therapeutics (ASCPT), International Society for the Study of Xenobiotics (ISSX) and the International Brain Barriers Society. Kunal is a member of several IQ consortiums including MIDD Pilot Program WG, Transporters, Induction PBPK and Pediatric PBPK. He is the founder member and Chair of the ASCPT QP PBPK Community. He received the 2014 AAPS Pharmaceutical Research Meritorious Manuscript Award for a manuscript that was published in the same journal in 2012. He has actively published and given invited talks and conducted workshops at international conferences.

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ISSX Webinar Series: Evaluation of Inflammatory Effect on Renal Drug Transporter Expression Using Human Kidney Biopsies and 3D-RPTECs

09/28/2026 at 5:00 PM (EDT) | 60 minutes

09/28/2026 at 5:00 PM (EDT) | 60 minutes In patients with renal impairment, tubular secretion of drugs via drug transporters is reduced. As a possible mechanism, the chronic inflammatory state associated with renal injury may affect the expression and activity of drug transporters. However, the relationship between inflammatory status and drug transporter expression have not been clarified using patient samples. In this study, we analyzed the expression levels of drug transporters in human kidney specimens and examined the effects of inflammatory cytokines on the expression and activity of renal drug transporters, organic anion transporter (OAT) 1 and 3, using three-dimensionally cultured human proximal tubular epithelial cells (3D-RPTEC) [1,2]. Proteomic analysis of non-tumor portion specimens of kidneys removed from patients with renal tumors revealed 93 transporters including OAT1. Enrichment analysis of proteins negatively correlated with OAT1 and OAT3 expression in human kidney using Metascape revealed GO terms related to inflammation. To characterize the direct effects of inflammatory cytokines on RPTECs, IL-1β and TNFα were exposed to 3D-RPTECs. As a result, mRNA expression of OAT1 and OAT3 was decreased and the uptake activity of the OAT1 substrate [3H] PAH was reduced. The decrease in mRNA expression due to inflammatory cytokine exposure was suppressed by the addition of the NF-κB inhibitor benzoxathiole. In conclusion, our studies revealed that inflammatory cytokines negatively regulate the expression of renal drug transporters OAT1 and OAT3.