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Neuronal apoptosis inhibitory protein is expressed in developing kidney and is regulated by PAX2

¹Department of Human Genetics, McGill University, Montreal Children's Hospital Research Institute, Montreal, Quebec; ²Department of Pediatrics, McGill University, Montreal Children's Hospital 2300 Tupper, Montreal, Quebec; ⁴Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada; and ³Department of Pathology, University of Otago, Hercus Building, Dunedin, New Zealand

Submitted 5 January 2006 ; accepted in final form 9 May 2006

During fetal kidney development, the extent of ureteric bud (UB) branching will determine final nephron endowment for life. Nephron number varies widely among normal humans and those who are born at the low end of the nephron number spectrum may be at risk for essential hypertension in adulthood. Little is known about how nephron number is set. However, we previously showed that the transcription factor, Pax2, suppresses apoptosis in UB cells during kidney development and optimizes branching morphogenesis. Here, we report that PAX2 directly binds to a specific recognition motif in the human neuronal apoptosis inhibitory protein (NAIP) gene promoter. NAIP is an endogenous inhibitor of apoptosis, inactivating caspase-3 and caspase-7 in neuronal tissues. PAX2 activates NAIP gene transcription (7-fold) in vitro and NAIP transcript level is increased fourfold in HEK293 cells stably transfected with PAX2. We show that Naip is expressed in embryonic day 15 (E15) fetal kidney tissue (RT-PCR) and NAIP protein is demonstrated by immunohistochemistry in E15 mouse kidney collecting ducts and P1 proximal tubules. Naip mRNA is significantly reduced (50%) in heterozygous Pax2 mutant mice. Finally, we show that an antisense Naip1 cDNA transfected into murine collecting duct cells doubles caspase-3/7 activity induced by Bax. These observations suggest that the powerful effects of PAX2 on renal branching morphogenesis and final nephron number may be mediated by activation of Naip which then suppresses apoptosis in UB cells.

Naip (Birc1); kidney development; renal hypoplasia

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