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PMID:16735463

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Citation

Dziarmaga, A, Hueber, PA, Iglesias, D, Hache, N, Jeffs, A, Gendron, N, Mackenzie, A, Eccles, M and Goodyer, P (2006) Neuronal apoptosis inhibitory protein is expressed in developing kidney and is regulated by PAX2. Am. J. Physiol. Renal Physiol. 291:F913-20

Abstract

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 Baxalpha. 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.

Links

PubMed Online version:10.1152/ajprenal.00004.2006

Keywords

Animals; DNA Primers; Embryonic Development; Gene Expression Regulation, Developmental; Gestational Age; Humans; Kidney/embryology; Kidney/physiology; Mice; Mice, Knockout; Mice, Mutant Strains; Nephrons/physiology; Neuronal Apoptosis-Inhibitory Protein/genetics; PAX2 Transcription Factor/deficiency; PAX2 Transcription Factor/genetics; PAX2 Transcription Factor/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Ureter/enzymology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PAX2

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PAX2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:B2L11

involved_in

GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BIR1A

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:BIR1A

located_in

GO:0016323: basolateral plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:BIR1A

enables

GO:0043027: cysteine-type endopeptidase inhibitor activity involved in apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:BIR1A

involved_in

GO:0043154: negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BIR1A

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAX

involved_in

GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PAX2

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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