BACKGROUND/AIM: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. METHODS: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. RESULTS: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. CONCLUSIONS: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.
BACKGROUND/AIM: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. METHODS: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. RESULTS: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. CONCLUSIONS: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.
Authors: Danielle L Brooks; Amanda E Garza; Isis A Katayama; Jose R Romero; Gail K Adler; Luminita H Pojoga; Gordon H Williams Journal: Endocrinology Date: 2019-04-01 Impact factor: 4.736
Authors: Danielle L Brooks; Amanda E Garza; Ezgi Caliskan Guzelce; Shadi K Gholami; Thitinan Treesaranuwattana; Stephen Maris; Sanjay Ranjit; Chee Sin Tay; Jessica M Lee; Jose R Romero; Gail K Adler; Luminita H Pojoga; Gordon H Williams Journal: Endocrinology Date: 2020-05-01 Impact factor: 4.736
Authors: Jurjen Zandstra; Marike M van Beuge; Johan Zuidema; Arjen H Petersen; Mark Staal; Luisa F Duque; Sergio Rodriguez; Audrey A R Lathuile; Gert J Veldhuis; Rob Steendam; Ruud A Bank; Eliane R Popa Journal: Pharm Res Date: 2015-05-09 Impact factor: 4.200
Authors: Reza Aghamohammadzadeh; Ying-Yi Zhang; Thomas E Stephens; Elena Arons; Paula Zaman; Kevin J Polach; Majed Matar; Lai-Ming Yung; Paul B Yu; Frederick P Bowman; Alexander R Opotowsky; Aaron B Waxman; Joseph Loscalzo; Jane A Leopold; Bradley A Maron Journal: FASEB J Date: 2016-03-22 Impact factor: 5.191