MOLECULAR BACKGROUND OF NSAID INDUCED RENAL AND INTESTINAL DAMAGE
Samaneh Haghighi
Theoretical and Translational Medicine Division
Dr. Kellermayer Miklós
NET Zöld előadóterem
2026-06-26 14:30:00
Translational kidney research and organ transplantation
Dr. Zsembery Ákos
Dr. Kökény Gábor
Dr. Zsigrai Sára
Dr. Sági Balázs
Dr. Váráshelyi Barna
Dr. Cserepkál Orsolya
Dr. Szinyákovics Janka
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications worldwide. Although effective for pain and inflammation, their prolonged or high-dose use is associated with significant nephrotoxicity and enteropathy. This PhD thesis investigates the molecular mechanisms underlying NSAID-induced renal fibrosis and small intestinal damage, focusing especially on pathways independent of cyclooxygenase (COX) inhibition.
The main objectives were: (1) to elucidate the effects of NSAIDs (celecoxib, naproxen, and indomethacin) on autophagy, oxidative stress, and pro-fibrotic signaling (particularly EGR1) in renal tubular epithelial cells and rat kidney; (2) to optimize cell culture conditions for reliable modeling of TGF-β1-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells; and (3) to characterize changes in intestinal antimicrobial peptides (AMPs) and systemic hematological parameters in indomethacin-induced enteropathy in rats.
In vitro and in vivo experiments showed that high-dose celecoxib and naproxen induce dose-dependent cytotoxicity, upregulate pro-fibrotic genes (TGFB1, COL1A1, TIMP1, ACTA2), activate EGR1 and AP-1 transcription factors, impair autophagic flux (increased LC3-II/I ratio accompanied by p62 accumulation), and trigger oxidative stress responses (elevated HMOX1 and pAKT) in renal tubular cells and kidney medulla. These effects occur largely independent of COX inhibition. DMEM with 5% FBS was identified as the optimal culture medium for consistent TGF-β1-induced EMT modeling in HK-2 cells. In vivo, prolonged administration led to mild tubular dilation, atrophy, and activation of fibrotic signaling in the renal medulla.
In the enteropathy model, indomethacin caused upregulation of cathelicidin (Camp) expression in the small intestine in both acute and chronic settings, with variable responses in α- and β-defensins. Systemic hematological changes (anemia and increased platelet parameters) reflected significant mucosal injury and inflammation.
Conclusions: This thesis demonstrates novel COX-independent mechanisms of NSAID toxicity, highlighting autophagy impairment and EGR1-mediated pro-fibrotic signaling as key contributors to renal injury, alongside disrupted antimicrobial peptide defense in NSAID-induced enteropathy. The findings provide new insights into NSAID safety and suggest potential therapeutic targets such as restoration of autophagy, modulation of EGR1, and regulation of antimicrobial peptides to mitigate organ damage in vulnerable patients.
Novelty of the Thesis:
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Identification of culture medium formulation as a critical determinant for reproducible EMT modeling in HK-2 cells.
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Elucidation of COX-independent renal effects of selective NSAIDs through autophagy disruption and EGR1 activation.
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Characterization of differential antimicrobial peptide responses and systemic biomarkers in NSAID-induced enteropathy.
