Renal Cyst Development in Mice with Conditional Inactivation of the von Hippel-Lindau Tumor Suppressor

Abstract

Inactivation of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic renal cysts and renal cell carcinoma, which are commonly thought to arise from the renal proximal tubule. pVHL regulates the protein stability of hypoxia-inducible factor (HIF)-A subunits and loss of pVHL function leads to HIF stabilization. The role of HIF in the development of VHL-associated renal lesions remains to be determined. To investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal epithelial cells, we used the phosphoenolpyruvate carboxykinase (PEPCK) promoter to generate transgenic mice in which Cre-recombinase is expressed in the renal proximal tubule and in hepatocytes. We found that conditional inactivation of VHL in PEPCK-Cre mutants resulted in renal cyst development that was associated with increased erythropoietin levels and polycythemia. Increased expression of the HIF target gene erythropoietin was limited to the liver, whereas expression of carbonic anhydrase 9 and multidrug resistance gene 1 was up-regulated in the renal cortex of mutant mice. Inactivation of the HIF-A binding partner, arylhydrocarbon receptor nuclear translocator (Arnt), but not Hif-1a, suppressed the development of renal cysts. Here, we present the first mouse model of VHL-associated renal disease that will provide a basis for further genetic studies to define the molecular events that are required for the progression of VHL-associated renal cysts to clear cell renal cell carcinoma. (Cancer Res 2006; 66(5): 2576-83)

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

“…However, a direct relationship between VHL status and response to (30,31). Furthermore, the absence of RCC tumorigenesis in VHLdeficient mice along with genetic data collected from humans suggests that RCC development likely requires additional cofactors that may synergize with VHL loss to trigger oncogenic transformation (32)(33)(34). Interestingly, increased survivin levels were recently reported to be associated with hypoxia (35).…”

Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury

“…Global S1pr1 deficiency is embryonically lethal. 30 PepckCreS1P1 fl/fl mice were generated by breeding S1pr1 fl/fl (generously provided by Dr. Richard L. Proia, NIH) and PepckCre mice (a kind gift of Dr. Volker Haase, Vanderbilt University) 46 as previously described 13 and littermates with WT S1pr1 alleles were used as controls. Mice were maintained on a standard diet and water was freely available.…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…The role of HIF-signaling during development is largely unclear, but the cell type-and stage-specific expression distribution of HIF-α subunits correlates with the expression of critical angiogenic factors such as VEGF and endoglin (Freeburg and Abrahamson 2003;Bernhardt et al 2006). Conditional knockouts in renal proximal tubule cells of either HIF-1α or HIF-β alone do not generate an abnormal phenotype, whereas conditional knockout of pVHL results in HIF-dependent development of tubular and glomerular cysts (Rankin et al 2006).…”