title: Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury.
abstract: OBJECTIVE
  All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis.
  
  
  METHODS
  The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin-aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment.
  
  
  RESULTS
  Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, -0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, -0.773, -0.769, -0.841, -0.794, -0.826; each p < 0.05), but positively correlated with ACE2, SOD, and GSH (PHB1: r = 0.796, 0.879, 0.824; PHB2: r = 0.785, 0.914, 0.849; each p < 0.05). ACE1 was positively correlated with angiotensin I, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA, and negatively correlated with ACE2, SOD, and GSH (each p < 0.05). ACE2 was negatively correlated with ACE1, angiotensin I, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA, and positively correlated with SOD and GSH (each p < 0.05).
  
  
  CONCLUSIONS
  The results suggest that ATRA acts as a positive regulator of PHB1, PHB2 and ACE2, and as a negative regulator of ACE1, angiotensin I, and angiotensin II in a RTEC model system under hypoxia/reoxygenation conditions.
authors.affiliation: Department of Nephrology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China a126tianbiao@126.com.
authors.forename: Tian-Biao
authors.initials: TB
authors.lastname: Zhou
authors.affiliation: Department of Experimental Pathology, The Affiliated Tumor Hospital of Guangxi Medical University, NanNing China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ou
authors.affiliation: Department of Pediatric-neonatology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Rong
authors.affiliation: Cellular Stress and Ageing Program, Bionanoscience and Bio-Imaging Program, Bio & Nano-Solutions, Düsseldorf, Germany.
authors.forename: Gregor P C
authors.initials: GP
authors.lastname: Drummen
mesh_terms: D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005353:Fibronectins / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D000091402:Prohibitins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; C000717332:Phb protein, rat; D000091402:Prohibitins; D012333:RNA, Messenger; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D014212:Tretinoin; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A
keywords: All-trans retinoic acid; angiotensin-converting enzyme 1; angiotensin-converting enzyme 2; extracellular matrix; fibrosis; oxidative stress; prohibitin 1; prohibitin 2; renal tubular epithelial cell; transforming growth factor-β1