of RCC. These data bare implications for improved understanding of cellular control of HIF expression and its effects, as well as development and progression of kidney disease. Renal tubular HIF expression We show that the distinct expression pattern for HIF-1a and HIF-2a in 
the kidney is stable across species and whatever stimulus is used. The molecular mechanism of differential control of HIFa expression remains elusive, where transcriptional, translational or posttranslational mechanisms could contribute. Importantly, when VHL is inactivated in renal tubular cells in mice or human VHL disease, we do see HIF-2a expression in these cells. The same has been described previously in another conditional VHL deletion model, although the authors did not compare the HIF-2a expression to microenvironmental stimulation. This could mean, that VHL in some way specifically suppresses the expression of HIF-2a in tubular epithelial cells, which may have interesting implications for renal tumorigenesis. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22180839 This is further supported by our findings in the early renal lesions of the human VHL disease. Type II foci show expression of HIF-2a, which is followed by upregulation of the proliferative target gene cyclin D1, which has been implicated in renal tumorigenesis before. Accordingly, early studies have described a VHL dependent expression in RCC cells, which was more inclined to influence HIF-2a, rather than HIF-1a. event in the development of RCC. Nevertheless, our data also show that HIF-2a activation on its own is not sufficient to induce renal tumors in the mouse, which is similar to two further murine models who have deleted VHL in tubular cells. The lack of tumors in our and most other mouse models may be a result of the absence of crucial additional oncogenic events. Accordingly, it has been estimated that ABT-450 biological activity numerous mutational events are necessary to establish a malignant tumor, which is capable of enforcing itself in a hostile microenvironment. However, HIF-1a overexpression in the proximal tubule seems sufficient to induce tumors in mice. Thus, the particular segment of the renal tubule may also be of importance. Renal cystic disease Regulation of renal tubular cell polarity and proliferation is strongly linked with the functional integrity of the primary cilium and ciliary defects often cause the development of renal cysts. Intriguingly, recent data have shown that VHL and/or HIF play an important role in ciliary biology. Consequently, two studies have demonstrated the development of renal cysts when VHL is inactivated in tubular cells with or without consecutive deletion of PTEN, respectively. It is not clear from these studies, which HIFa isoform mainly contributed to cyst development, although one study suspected HIF-2a to be the driving force, since simultaneous HIF-2a knockouts did not show cysts. In human autosomal dominant polycystic kidney disease HIF is also activated, but follows the ��physiological��expression pattern of tubular HIF-1a and peritubular HIF-2a. Of note, primary cystic diseases such as ADPKD rarely show the development of RCC, whereas acquired renal cysts and cysts in the hereditary VHL syndrome are regarded as precancerous lesions. Whether the reason for these differences lie within HIF-2a expression of cystic epithelia remains speculative to date and is under investigation. Renal cell carcinoma The development of VHL associated clear cell RCC appears to be closely linked to HIF activation. It has been demonstrated that
