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Rescue of Defective Branching Nephrogenesis in Renal-Coloboma Syndrome by the Caspase Inhibitor, Z-VAD-fmk

Patsy Clark^*, Alison Dziarmaga^*, Michael Eccles^, and Paul Goodyer^*,

*Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Pathology, University of Otago, Dunedin, New Zealand; Department of Pediatrics, McGill University, Montreal, Quebec, Canada.

Correspondence to Dr. Paul Goodyer, McGill University Montreal Children’s Hospital, 2300 Tupper Street, Room E222A, Montreal, Quebec, Canada H3H 1P3. Phone: 514-412-4400 ext 22584; Fax: 514-412-4359; E-mail: Paul.Goodyer{at}muhc.mcgill.ca

ABSTRACT. In renal-coloboma syndrome (RCS), null mutations of the PAX2 gene cause renal hypoplasia due to a congenital deficit of nephrons; affected individuals may develop renal insufficiency in childhood. During normal kidney development, PAX2, is expressed at high levels throughout the arborizing ureteric bud (UB); recent observations suggest that one of its key roles is to suppress apoptosis in this collecting duct lineage. The authors hypothesized that increased UB cell apoptosis due to PAX2 haploinsufficiency must directly influence the rate of branching morphogenesis in developing kidney and the number of nephrons that can be formed before birth, when nephrogenesis in humans comes to an end. If so, the authors reasoned that caspase inhibitors might be used to suppress unwanted UB cell apoptosis during kidney development in Pax2^1Neu mutant mice and rescue the genetic UB branching defect. E17.5 kidneys from Pax2^1Neu mutant mice had smaller (-25%) longitudinal cross-sectional area and 3.5-fold increase in collecting duct cell apoptosis versus wild-type littermates; mutant E13.5 kidney explants allowed to arborize for 50 h in vitro had 18% fewer terminal branches than wild-types. However, exposure to the caspase inhibitor, Z-VAD-fmk (25 µM), significantly increased terminal branch number in mutant explants (23%). It also increased branching in wild-type explants, apparently reflecting an effect of Z-VAD-fmk on basal apoptosis induced by ex vivo culture conditions. Similarly, when pregnant mice were injected daily with Z-VAD-fmk (10 µg/g weight from E10.5 to E17.5), apoptosis of Pax2^1Neu fetal collecting duct cells was suppressed to 40% of untreated mutants; by E14, terminal branch number was increased to 152% that of untreated litters. These studies support the hypothesis that PAX2 normally optimizes the rate of branching morphogenesis in fetal kidney by suppressing UB apoptosis. Furthermore, it suggests that caspase inhibitors can rescue the branching defect caused by PAX2 mutations.

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