o:37543 Olive Leaf Extract Added to Losartan Treatment Improved Klotho/Wnt/β-Catenin Signaling in Hypertensive Rats with Focal Segmental Glomerulosclerosis en The downregulation of Klotho in renal injury predicts the progression of chronic kidney disease (CKD). Klotho acts as an antagonist of the Wnt/β-catenin pathway, which is involved in the pathogenesis of proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. We investigated whether losartan (L, angiotensin II type-1 receptor blocker) alone or combined with synthetic (tempol, T) or natural antioxidants (olive leaf extract, O) could alter Klotho/Wnt4/β-catenin signaling, thus reducing fibrosis and slowing the progression of focal segmental glomerulosclerosis (FSGS) in spontaneously hypertensive rats (SHR). The rats were divided into five groups. The control rats received a vehicle. The other groups received adriamycin (2 mg/kg, i.v., twice in a 3-week interval) for FSGS induction. Treatments with L, L+T and L+O (10, 10 + 100 and 10 + 80 mg/kg/day, respectively) were administered by gavage during six weeks. In the kidneys of model rats, Klotho and Wnt4 were downregulated, whereas β-catenin and fibronectin levels were increased compared with the control group. L+T did not alter Klotho, Wnt4 or fibronectin levels, while it further increased β-catenin. In contrast, L+O improved Klotho, and reduced β-catenin and fibronectin levels, although it increased PAI-1. The L+O combination reduced proteinuria more efficiently than L and decreased renal injury close to control levels. Although these findings indicate that combined treatment of losartan and olive leaf extract is promising in slowing the progression of the experimental FSGS, further clinical studies are needed to confirm its favorable outcomes and safety in CKD patients. Klotho; Wnt/β-catenin signaling; tempol; olive leaf extract; hypertensive rats; focal segmental glomerulosclerosi 1552099 https://doi.org/10.3390/antiox15010146 2026-01-23T08:52:44.440Z 44 yes 46 Danijela Karanović Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia Nevena Mihailović-Stanojević Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia person Milan Ivanov Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia person Una-Jovana Vujačić Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia person Jelica Grujić-Milanović Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia person Maja Životić Institute of Pathology “Dr. Ðorđe Joannović”, Faculty of Medicine, University of Belgrade, Dr Subotića 1, 11000 Belgrade, Serbia person Dragana Dekanski Department for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia doktor medicinskih nauka person 0000-0001-8467-4165 Đurđica Jovović Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia person Zoran Miloradović Department for Cardiovascular Physiology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr Subotića 4, P.O. Box 39, 11129 Belgrade, Serbia person application/pdf 4079576 https://phaidrabg.bg.ac.rs/o:37543 no yes 16 70 92000001 11A25 11A2503 11A29 11A2901 Olive Leaf Extract Added to Losartan Treatment Improved Klotho/Wnt/β-Catenin Signaling in Hypertensive Rats with Focal Segmental Glomerulosclerosis 146 15 1 Antioxidants Basel, Switzerland MDPI 2026