Citation: Zivotic, M.; Dundjerovic, D.; Naumovic, R.; Kovacevic, S.; Ivanov, M.; Karanovic, D.; Nikolic, G.; Markovic-Lipkovski, J.; Radojevic Skodric, S.; Nesovic Ostojic, J. Clinicopathological Relevance of PAX8 Expression Patterns in Acute Kidney Injury and Chronic Kidney Diseases. Diagnostics 2022, 12, 2036. https://doi.org/10.3390/ diagnostics12092036 Academic Editor: Mauro Giuseppe Mastropasqua Received: 29 June 2022 Accepted: 17 August 2022 Published: 23 August 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). diagnostics Article Clinicopathological Relevance of PAX8 Expression Patterns in Acute Kidney Injury and Chronic Kidney Diseases Maja Zivotic 1,† , Dusko Dundjerovic 1,† , Radomir Naumovic 2 , Sanjin Kovacevic 3 , Milan Ivanov 4 , Danijela Karanovic 4 , Gorana Nikolic 1 , Jasmina Markovic-Lipkovski 1 , Sanja Radojevic Skodric 1, * and Jelena Nesovic Ostojic 3, * 1 Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia 2 Clinic of Nephrology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia 3 Institute of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia 4 Institute for Medical Research, Department of Cardiovascular Physiology, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia * Correspondence: sanja.radojevic-skodric@med.bg.ac.rs (S.R.S.); jelena.nesovic-ostojic@med.bg.ac.rs (J.N.O.) † These authors contributed equally to this work. Abstract: Transcription factor PAX8, expressed during embryonic kidney development, has been previously detected in various kidney tumors. In order to investigate expression of PAX8 transcription factor in acute kidney injury (AKI) and chronic kidney diseases (CKD), immunohistochemical analysis was performed. Presence, location and extent of PAX8 expression were analyzed among 31 human kidney samples of AKI (25 autopsy cases, 5 kidney biopsies with unknown etiology and 1 AKI with confirmed myoglobin cast nephropathy), as well as in animals with induced postischemic AKI. Additionally, expression pattern was analyzed in 20 kidney biopsy samples of CKD. Our study demonstrates that various kidney diseases with chronic disease course that results in the formation of tubular atrophy and interstitial fibrosis, lead to PAX8 expression in the nuclei of proximal tubules. Furthermore, patients with PAX8 detected within the damaged proximal tubuli would be carefully monitored, since deterioration in kidney function was observed during follow-up. We also showed that myoglobin provoked acute kidney injury followed with large extent of renal damage, was associated with strong nuclear expression of PAX8 in proximal tubular cells. These results were supported and followed by data obtained in experimental model of induced postischemic acute kidney injury. Considering these findings, we can assume that PAX8 protein might be involved in regeneration process and recovery after acute kidney injury. Thus, accordingly, all investigation concerning PAX8 immunolabeling should be performed on biopsy samples of the living individuals. Keywords: PAX8; human kidneys; acute kidney injury; chronic kidney disease 1. Introduction PAX8 is a member of the mammalian Paired-box family of genes that includes 9(PAX1–9) different genes and plays a crucial role in the organogenesis of the kidney, thyroid gland, and Müllerian organs [1–4]. The reactivation of embryonic genes has been observed during pathogenesis of many diseases [5]. Sometimes, initial activation of such condition serves as a counteracting mech- anism in order to diminish damaging signal and to improve wound healing [6,7]. However, the line between beneficial and adverse reactions could be loose, since constitutive activity of embryonic gene program during persistent alteration would also impair regeneration tissue efforts. Among various embryonic genes expressed during kidney development, the funda- mental role in branching morphogenesis and nephron differentiation belongs to PAX8 tran- scription factor [8]. Nuclear transcription factor PAX2 expressed by proliferating stem cells, Diagnostics 2022, 12, 2036. https://doi.org/10.3390/diagnostics12092036 https://www.mdpi.com/journal/diagnostics