Deregulation of cell survival in cystic and dysplastic renal development

Abstract

Various aberrations of cell biology have been reported in polycystic kidney diseases and in cystic renal dysplasias. A common theme in these disorders is failure of maturation of renal cells which superficially resemble embryonic tissue. Apoptosis is a feature of normal murine nephrogenesis, where it has been implicated in morphogenesis, and fulminant apoptosis occurs in the small, cystic kidneys which develop in mice with null mutations of bcl-2. Therefore, we examined the location and extent of apoptosis in pre- and postnatal samples of human polycystic and dysplastic kidney diseases using propidium iodide staining, in situ end-labeling and electron microscopy. In dysplastic kidneys cell death was prominent in undifferentiated cells around dysplastic tubules and was occasionally found in cystic epithelia. The incidence of apoptosis was significantly greater than in normal controls of comparable age both pre- and postnatally. In the polycystic kidneys there was widespread apoptosis in the interstitium around undilated tubules distant from cysts, in undilated tubules between cysts and in cystic epithelia. The level of apoptosis compared to controls was significantly increased postnatally. A similar increase of cell death was also noted in the early and late stages of renal disease in the polycystic cpk/cpk mouse model. We speculate that deregulation of cell survival in these kidneys may reflect incomplete tissue maturation, and may contribute to the progressive destruction of functional kidney tissue in polycystic kidneys and the spontaneous involution reported in cystic dysplastic kidneys.

Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

“…In the pcy kidney, abundant apoptotic cells were observed in the interstitium and occasionally in the cyst epithelium ( Figure 2D). These findings are consistent with the results of previous studies in other animal models of PKD as well as in human PKD (8,9).…”

“…That JNK is not expressed in the normal immature kidney or in the epithelium of cysts in dysplastic kidneys suggests a role of JNK in differentiation at a later stage (4,6). Our study showed that the cyst epithelium of pcy mice has the same pattern of dysregulated MAPK expression as that of dysplasia and increased expression of PCNA and apoptosis in the cyst epithelium, a common feature of cystic diseases (7,8). Cyst epithelium in PKD is thought to have a persistent developmental phenotype as evidenced by altered expression of PAX2, vimentin, clusterin, Na ϩ /K ϩ -ATPase, and the EGF receptor (14).…”

“…Pax2 is a transcription factor that plays an important role during kidney development, and the expression and the function of p38 and ERK in dysplasia and PKD are reminiscent of those of Pax2. Pax2 is thought to be required for mesenchymal cell growth and prevention of apoptosis (15,16) and has been found to be overexpressed in cyst epithelium of both dysplasia and PKD (8). The reduced Pax2 gene dosage reduced cyst formation in cpk mice, a murine model of rapid-onset PKD (17).…”

“…The epithelium of the cysts in PKD exhibits similar features to those of dysplastic epithelium: Increased proliferation; apoptosis; and expression of a transcription factor, PAX2 (7)(8)(9). In this study we investigated the expression of MAPK in DBA/2-pcy/pcy (pcy) mice, a murine model of childhood PKD, juvenile nephronophthisis.…”

Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease

“…Increased levels of tubular cell apoptosis and proliferation are observed in human ADPKD (17)(18)(19), the cpk model of autosomal recessive PKD (19), the newly developed pck model of ADPKD (20), and dysplastic renal disease (21). Increased tubular cell apoptosis and proliferation are features of transgenic mice overexpressing the protooncogene c-myc (SBM mice) (22), mice lacking the transcription factor AP-2␤ (23), and Bcl-2-deficient mice (24).…”