Research Paper|Volume 16, Issue 22|pp 13588—13607

Impaired renal transporter gene expression and uremic toxin excretion as aging hallmarks in cats with naturally occurring chronic kidney disease

Qinghong Li¹, James A. Holzwarth², Bethany Smith³, Sonia Karaz², Mathieu Membrez², Vincenzo Sorrentino², Stacie Summers⁴, Julie Spears¹, Eugenia Migliavacca²

¹Nestlé Purina Research, St. Louis, MO 63102, USA
²Nestlé Research, Lausanne, Switzerland
³Nestlé Purina Research, St. Joseph, MO 64503, USA
⁴Oregon State University, Corvallis, OR 97331, USA

* Current address: Department of Biochemistry and Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Received: May 21, 2024Accepted: November 22, 2024Published: December 20, 2024

https://doi.org/10.18632/aging.206176

Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aging leads to nephron senescence and chronic kidney disease (CKD). In cats, indoxyl sulfate (IxS) has been previously quantified and associated with CKD, and little is known about tubular transporters. Two cohorts of cats aged 6 to 21 years were enrolled. Cohort 1 included 41 colony cats with 28 control and 13 CKD cats. Cohort 2 had 30 privately-owned cats with 10 control and 20 CKD cats. In cohort 1, serum concentrations of IxS, trimethylamine N-oxide (TMAO), p-cresol sulfate (PCS), and phenyl sulfate were higher in CKD vs. control cats (all P<0.05). This observation was independently validated in cohort 2. Renal cortical and medullar tissues were collected from a third cohort of cats euthanized for humane reasons unrelated to the study. We provided the evidence that renal tubular transporter genes, OAT1, OAT4, OATP4C1, and ABCC2, but not OAT3, were expressed in the kidneys of cats, and their expressions were downregulated in CKD (all FDR<0.1). Cats and humans share 90.9%, 77.8%, and 82.5% identities in OAT1, OATP4C1, and ABCC2 proteins, respectively. In healthy cats, circulating TMAO and IxS are significantly correlated with age. Our study reveals impaired uremic toxin secretion and tubular transporter expression in cats with CKD.