title: Angiotensin II stimulates Pax-2 in rat kidney proximal tubular cells: impact on proliferation and apoptosis.
abstract: BACKGROUND
  The intrarenal renin-angiotensin system (RAS) is intimately involved in the tubular cell proliferation, apoptosis and regeneration that occur following renal injury. Though tubular angiotensin II (Ang II) type 2 receptors (AT2R) decrease greatly after birth, their number increases after injury. Notably, during recovery from injury, renal tubular cells display a relatively immature phenotype expressing genes that are involved in nephron development, for example, the paired homeobox-2 gene (Pax-2). The present investigation hypothesized that AT2R activation would stimulate Pax-2 gene expression in immortalized rat renal proximal tubular cells (IRPTC), as we have found in fetal cells.
  
  
  METHODS
  Pax-2 gene expression in IRPTC was evaluated by immunofluorescence, Western blot, reverse transcription-polymerase chain reaction (RT-PCR) with or without Ang II treatment; apoptosis and proliferation were analyzed by terminal transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay and bromodeoxyuridine (BrdU) incorporation in stable IRPTC transformants with Pax-2 sense and antisense orientation, respectively.
  
  
  RESULTS
  Ang II up-regulated Pax-2 gene expression via AT2R in IRPTC. The stimulatory effect of both Ang II on Pax-2 gene expression was blocked by PD123319 (AT2R inhibitor), AG 490 (specific Janus kinase 2 (JAK2) inhibitor) and genistein (tyrosine kinase inhibitor), but not by losartan (AT1R inhibitor). Stable transfection of sense Pax-2 cDNA increased, whereas antisense Pax-2 cDNA down-regulated Pax-2 expression.
  
  
  CONCLUSIONS
  Our studies suggest that Ang II stimulates Pax-2 gene expression in IRPTC via AT2R and the JAK2/signal transducers and activators of transcription (STAT) signaling transduction pathway, which may be important in renal repair following injury. Cells lacking Pax-2 gene expression appear to be prone toward apoptosis rather than proliferation.
authors.affiliation: Pediatric Nephrology Unit, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114-3117, USA.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Babak
authors.initials: B
authors.lastname: Moini
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D019833:Genistein / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D053614:Janus Kinase 2; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051762:PAX2 Transcription Factor; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014170:Transformation, Genetic; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D051762:PAX2 Transcription Factor; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D014157:Transcription Factors; D020032:Tyrphostins; D014662:Vasoconstrictor Agents; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; C073402:PD 123319; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2