Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD).
The proto-oncogene c-myc has been implicated in both cellular proliferation and apoptosis, and we have shown that overexpression of c-myc can induce polycystic kidney disease in transgenic mice. To elucidate the molecular and cellular defects underlying cystogenesis, we have investigated the potential roles of cell proliferation and apoptosis as they relate to c-myc and modulators of c-myc function in human autosomal dominant polycystic kidney disease (ADPKD). Renal c-myc expression was consistently elevated, up to 15-fold, in ADPKD. High levels of c-myc expression correlated with 10- to 100-fold increased proliferation index in cystic epithelium. Interestingly, steady-state levels of bcl-2 mRNA were also increased up to 20-fold and Bcl-2 protein was markedly elevated. In contrast, the expression of bax and p53 was virtually unchanged. However, apoptosis was consistently and significantly increased in ADPKD kidneys, unchecked by high levels of Bcl-2. Together with proliferation, apoptosis may thus represent a general mechanism for cyst growth and tissue remodeling. We conclude that both epithelial cell proliferation and apoptosis required for normal kidney homeostasis are deregulated in ADPKD, recapitulating the renal developmental program. Furthermore, abnormal expression of proto-oncogenes regulating these processes is an important mediator of cystogenesis in human ADPKD.
Lanoix
J
J
Institut de Recherches Cliniques de Montréal, Faculté de Médicine del'Université de Montréal, Québec, Canada.
D'Agati
V
V
Szabolcs
M
M
Trudel
M
M
D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D012313:RNA