Hormones – Cytokines – Signalling
Kidney International (2004) 66, 2181–2192; doi:10.1111/j.1523-1755.2004.66008.x
Angiotensin II stimulates Pax-2 in rat kidney proximal tubular cells: Impact on proliferation and apoptosis
SHAO-LING ZHANG, JUN GUO, BABAK MOINI and JULIE R INGELFINGER
Pediatric Nephrology Unit, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts; and Endocrinology Unit, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts
Correspondence: Julie R. Ingelfinger, M.D., Pediatric Nephrology Unit, Harvard Medical School, Masssachusetts General Hospital, 55 Fruit Street, BHX-411, Boston, MA 02114-3117. E-mail:jingelfinger@partners.org
Received 4 March 2004; Revised 17 May 2004; Re-revised 11 June 2004; Accepted 22 June 2004.
Abstract
Angiotensin II stimulates Pax-2 in rat kidney proximal tubular cells: Impact on proliferation and apoptosis.
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.
Conclusion
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.
Keywords:
Pax-2, angiotensin II, apoptosis, proximal tubular cells
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