PAX2 is reactivated in urinary tract obstruction and partially protects collecting duct cells from programmed cell death

Abstract

Obstruction of the urinary tract activates apoptotic pathways in collecting duct cells and leads to loss of renal parenchyma before surgical intervention. It has been suggested that developmental pathways may be reactivated to offset acute organ damage. One such molecule, PAX2, is expressed throughout the fetal collecting duct and was recently shown to suppress apoptosis during kidney development. We hypothesized that acute unilateral urinary tract obstruction (UUO) reactivates PAX2 expression in the mature kidney and partially suppresses apoptosis. If so, animals with PAX2 mutations should have increased susceptibility to parenchymal damage. Wild-type and heterozygous Pax2 mutant (C3H/ Pax2 1Neu) mice underwent unilateral ureteric ligation or sham operation at 6 wk of age; kidneys were examined after 5, 10, and 15 days. Whereas PAX2 protein levels fell to low levels in the first weeks of life, it was sharply reactivated by day 10 in collecting duct cells of wild-type but not in Pax2 1Neu mutant mice with UUO. Wild-type mice with UUO had marked TUNEL and cleaved spectrin staining in tubular cells and reduced kidney weight after 10–15 days. Mutant mice had exaggerated increases in markers of apoptosis and exaggerated loss of renal parenchymal loss in the obstructed kidney. These observations suggest that PAX2 is rapidly reactivated in UUO and that mice with genetically limited PAX2 expression have heightened susceptibility to apoptosis.

Expression pattern of PAX2 in hyperplastic and malignant endometrium

“…To explain this Wnding, some speculations can be made on the basis of kidney investigations. It was suggested that the increased PAX2 expression in urinary tract obstructions can be related with the antiapoptotic role of PAX2, taking place to prevent atrophy [22]. The anti-apoptotic eVect of PAX2 was shown to be the result of the transcriptional activation of the neural apoptosis inhibitory protein gene [23].…”

Pax genes in renal development, disease and regeneration

“…Some work suggests that Pax2 uses the same set of functions during kidney repair as it does during development ( Figure 3). Particularly, it has been Page 18 of 36 A c c e p t e d M a n u s c r i p t found that Pax2 inhibits apoptosis of tubular renal cells during the initial stage of regeneration [115,118,119]. Other studies suggest that Pax2 may be implicated in epithelial to mesenchymal transition of epithelial tubular cells and confers a mesenchymal stem cell-like progenitor phenotype on those cells, which is required for proper re-differentiation during kidney repair [89,91,120].…”

Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

“…[30][31][32][33][34][35] We used TUNEL labeling to assay apoptosis in kidneys obstructed for 1, 2, 3, 6, and 9 days. In sham-operated kidneys at all time points, TUNEL-positive cells were rare and scattered throughout the kidney (Figures 4a-c) and are indicative of the normal rate of cell turnover within the kidney.…”