Apoptotic loss of renal tissue may be associated with the progressive deterioration of renal function that occurs in patients with polycystic kidney disease.

Myc requires de novo protein synthesis, indicating that repression is indirect. Importantly, the suppression of Bcl-2 or Bcl-X L by Myc is corrupted during Myc-induced tumorigenesis, as Bcl-2 and/or Bcl-X L levels are markedly elevated in over one-half of all lymphomas arising in E-myc transgenic mice. Bcl-2 and/or Bcl-X L overexpression did not correlate with loss of ARF or p53 function in tumor cells, indicating that these two apoptotic pathways are inactivated independently. Therefore, the suppression of Bcl-X L or Bcl-2 expression represents a physiological Myc-induced apoptotic pathway that is frequently bypassed during lymphomagenesis.

Polycystic kidney diseases (PKD) are the most common hereditary diseases of the human kidney and account for ten per cent of patients requiring renal transplantation or dialysis. Renal cyst formation has been attributed to enhanced cell proliferation, unbalanced cell death, abnormal targeting of membrane proteins, aberrant kidney development and tubular obstruction, but there is no treatment that blocks the formation and enlargement of renal cysts. We have now developed an in vitro model of spontaneous cyst formation that distinguishes polycystic kidney epithelium from its normal counterpart. Inhibitors of DNA, RNA and protein synthesis did not prevent in vitro cyst formation, but this was reversibly inhibited by ouabain, amiloride and the microtubule-specific agents colchicine, vinblastine and taxol. The cpk mouse is a well-characterized recessive PKD model and we find that cpk/cpk mice develop PKD and die from uraemia by 4-5 weeks of age, but when treated weekly with taxol they survive for more than 200 days with minimal loss of renal function, show limited collecting-dust cyst enlargement, and attain adult size. Our results indicate that the microtubule cytoskeleton has a central role in the pathogenesis of PKD in cpk mice and that taxol may also be useful in treating human PKD.

Unlike the uniform disease progression in inbred animals, polycystic kidney disease (PKD) progression within human families can be highly variable. This may be due to environmental or genetic factors or both. To determine if PKD severity can be influenced by modifier genes, we carried out an intercross between DBA/2-pcy/pcy and Mus m. castaneous involving 3,105 6-wk-old F2 mice. Large differences in PKD severity were observed in this cross. In addition, 23/ 800 phenotypically normal mice were pcy/pcy genotypically. These results demonstrated that PKD progression in pcy/ pcy mice is a quantitative trait that is strongly modulated by modifier genes. Whole genome quantitative trait loci mapping of 114 selected pcy/pcy mice (68 with the mild PKD and 46 with severe PKD) identified two loci, MOP1 and MOP2 that strongly modulate PKD progression. MOP1 (max LOD score ϭ 10.3 at D4Mit111) and MOP2 (max LOD score ϭ 13.8 at D16Mit1) accounted for 36.7 and 46.8% of the phenotypic variance, respectively. Two-factor ANOVA of the phenotypes and genotypes of all 673 pcy/pcy mice from our cross indicated that MOP1 and MOP2 alleles regulate PKD progression in a complex additive manner. Characterization of these novel modifying loci may provide additional insights into the pathogenesis of polycystic kidney diseases.

To examine the role of tubulointerstitial cell interaction in the regulation of fibroblast growth, fibroblasts from the rabbit renal cortex (CF) and papilla (PF) were cocultured with epithelial cells from the same tissue location. Inner medullary collecting duct epithelial cells (IMCDE) or IMCDE-conditioned medium stimulated DNA synthesis in PF, whereas proximal tubule epithelium (PTE) had no effect on the proliferation of CF. PF and CF showed a similar mitogenic response to exogenous epidermal growth factor and insulin-like growth factor 1 (IGF-I). Transforming growth factor-beta 1 inhibited growth of both cell types, and basic fibroblast growth factor (bFGF) had no effect on proliferation of either cell type. In contrast, platelet-derived growth factor (PDGF) was a potent mitogen for PF but was only weakly mitogenic for CF. Both CF and PF expressed a similar number of a single-affinity class of PDGF receptors (Kd, 2-4 x 10(-10) M). Assay for growth factor activity in conditioned medium from IMCDE and PTE showed that only IMCDE produced detectable PDGF. IMCDE-stimulated proliferation of PF was partially blocked by an antibody to PDGF, whereas antibodies to IGF-I had no neutralizing effect. The data suggest a role for PDGF in the regulation of interstitial fibroblast proliferation by IMCDE in the renal papilla. This paracrine system may be important in the pathogenesis of some forms of interstitial fibrosis of the kidney.