Linagliptin Mitigates TGF-β1 Mediated Epithelial–Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis via Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways

• Published in: Biological & pharmaceutical bulletin 2024/05/24, Vol.47(5), pp.1008-1020
• Main Authors: Nady, Mohamed E., El-Raouf, Ola M. Abd, El-Sayed, El-Sayed M.
• Format: Article
• Language: English
• Subjects: Actin; Animals; Blood levels; Diabetes; Diabetes mellitus; dipeptidyl peptidase-4 (DPP-4) inhibitor; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; E-cadherin; Enzyme-linked immunosorbent assay; Epithelial-Mesenchymal Transition - drug effects; epithelial–mesenchymal transition; Extracellular matrix; Extracellular signal-regulated kinase; Fibrosis; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunosuppressive Agents - pharmacology; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kinases; linagliptin; Linagliptin - pharmacology; Linagliptin - therapeutic use; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Molecular modelling; Olive oil; p38 Mitogen-Activated Protein Kinases - metabolism; Proteins; Rats; Rats, Sprague-Dawley; renal fibrosis; Renal function; Signal transduction; Signal Transduction - drug effects; Smad protein; Smad Proteins - metabolism; Smad4 protein; Smooth muscle; Tacrolimus; Tacrolimus - pharmacology; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Vimentin
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b23-00737

The dipeptidyl peptidase-4 (DPP-4) inhibitors, a novel anti-diabetic medication family, are renoprotective in diabetes, but a comparable benefit in chronic non-diabetic kidney diseases is still under investigation. This study aimed to elucidate the molecular mechanisms of linagliptin’s (Lina) protective role in a rat model of chronic kidney injury caused by tacrolimus (TAC) independent of blood glucose levels. Thirty-two adult male Sprague Dawley rats were equally randomized into four groups and treated daily for 28 d as follows: The control group; received olive oil (1 mL/kg/d, subcutaneously), group 2; received Lina (5 mg/kg/d, orally), group 3; received TAC (1.5 mg/kg/d, subcutaneously), group 4; received TAC plus Lina concomitantly in doses as the same previous groups. Blood and urine samples were collected to investigate renal function indices and tubular injury markers. Additionally, signaling molecules, epithelial–mesenchymal transition (EMT), and fibrotic-related proteins in kidney tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, immunohistochemical and histological examinations. Tacrolimus markedly induced renal injury and fibrosis as indicated by renal dysfunction, histological damage, and deposition of extracellular matrix (ECM) proteins. It also increased transforming growth factor β1 (TGF-β1), Smad4, p-extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P38/P38 mitogen-activated protein kinase (MAPK) protein levels. These alterations were markedly attenuated by the Lina administration. Moreover, Lina significantly inhibited EMT, evidenced by inhibiting Vimentin and α-smooth muscle actin (α-SMA) and elevating E-cadherin. Furthermore, Lina diminished hypoxia-related protein levels with a subsequent reduction in Snail and Twist expressions. We concluded that Lina may protect against TAC-induced interstitial fibrosis by modulating TGF-β1 mediated EMT via Smad-dependent and independent signaling pathways.