Telmisartan inhibits oxalate and calcium oxalate crystal-induced epithelial-mesenchymal transformation via PPAR-γ-AKT/STAT3/p38 MAPK-Snail pathway.
AIMS
Telmisartan (TLM), a highly selective angiotensin II type 1 receptor blocker (ARB) and partial PPAR-γ agonist, has versatile beneficial effects against oxidative stress, apoptosis, inflammatory responses and epithelial-mesenchymal transition (EMT). However, its underlying mechanism of inhibiting oxalate and calcium oxalate (CaOx) crystal-induced EMT by activating the PPAR-γ pathway remains unclear.


MAIN METHODS
CCK-8 assays were used to evaluate the effects of TLM on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were measured by the cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate (DCFH-DA). Wound-healing and Transwell assays were used to evaluate the migration ability of HK2 cells exposed to oxalate. Moreover, immunofluorescence, immunohistochemistry and western blotting were used to examine the expression of E-cadherin, N-cadherin, vimentin and α-SMA and explore the underlying molecular mechanisms in HK2 cells and a stone-forming rat model.


KEY FINDINGS
Our results showed that TLM treatment could protect HK2 cells from oxalate-induced cytotoxicity and oxidative stress injury. Additionally, TLM prevented EMT induction by oxalate and CaOx crystals via the PPAR-γ-AKT/STAT3/p38 MAPK-Snail pathway in vitro and in vivo. However, knockdown of PPAR-γ with small interfering RNA or the PPAR-γ-specific antagonist GW9662 abrogated these protective effects of TLM.


SIGNIFICANCE
As a PPAR-γ agonist, TLM can ameliorate oxalate and CaOx crystal-induced EMT by exerting an antioxidant effect through the PPAR-γ-AKT/STAT3/p38 MAPK-Snail signaling pathway. Therefore, TLM can block EMT progression and could be a potential therapeutic agent for preventing and treating calcium oxalate urolithiasis formation and recurrence.
['Liu|Yadong|Y|', 'Chen|Song|S|', 'Liu|Jiannan|J|', 'Jin|Yinshan|Y|', 'Yu|Shiliang|S|', 'An|Ruihua|R|']
D000818:Animals D002129:Calcium Oxalate D002460:Cell Line D058750:Epithelial-Mesenchymal Transition D006801:Humans D007684:Kidney Tubules D008297:Male D010070:Oxalates D018384:Oxidative Stress D047495:PPAR gamma D051057:Proto-Oncogene Proteins c-akt D017207:Rats, Sprague-Dawley D050796:STAT3 Transcription Factor D000071250:Snail Family Transcription Factors D000077333:Telmisartan D053773:Transforming Growth Factor beta1 D048051:p38 Mitogen-Activated Protein Kinases
Oxalate PPAR-γ-AKT/STAT3/p38 MAPK-Snail Telmisartan (TLM) EMT Calcium oxalate crystals (CaOx)