Dataset Information

Renal tubular HIF-2? expression requires VHL inactivation and causes fibrosis and cysts.

ABSTRACT: The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated ?-subunits HIF-1? or HIF-2?. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor "von Hippel-Lindau" (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO production, organ preservation from ischemia-reperfusion injury and renal tumorigenesis are prominent examples. Whereas HIF-1? is inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2? is never detected in these cells, in any species. In contrast, distinct early lesions of biallelic VHL inactivation in kidneys of the hereditary VHL syndrome show strong HIF-2? expression. Furthermore, knockout of VHL in the mouse tubular apparatus enables HIF-2? expression. Continuous transgenic expression of HIF-2? by the Ksp-Cadherin promotor leads to renal fibrosis and insufficiency, next to multiple renal cysts. In conclusion, VHL appears to specifically repress HIF-2? in renal epithelia. Unphysiological expression of HIF-2? in tubular epithelia has deleterious effects. Our data are compatible with dedifferentiation of renal epithelial cells by sustained HIF-2? expression. However, HIF-2? overexpression alone is insufficient to induce tumors. Thus, our data bear implications for renal tumorigenesis, epithelial differentiation and renal repair mechanisms.

SUBMITTER: Schietke RE

PROVIDER: S-EPMC3267769 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts.

Schietke Ruth E RE Hackenbeck Thomas T Tran Maxine M Günther Regina R Klanke Bernd B Warnecke Christina L CL Knaup Karl X KX Shukla Deepa D Rosenberger Christian C Koesters Robert R Bachmann Sebastian S Betz Peter P Schley Gunnar G Schödel Johannes J Willam Carsten C Winkler Thomas T Amann Kerstin K Eckardt Kai-Uwe KU Maxwell Patrick P Wiesener Michael S MS

PloS one 20120127 1

The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor "von Hippel-Lindau" (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO producti ...[more]

PMID: 22299048

Similar Datasets

Project description:BackgroundRenal fibrosis is the pathological foundation of various chronic kidney diseases progressing to end stage renal failure. However, there are currently no nephroprotective drugs targeted to the fibrotic process in clinical practice. Proteolytic targeting chimeras (PROTACs), which reversibly degrade target proteins through the ubiquitin-proteasome pathway, is a novel therapeutic modality. Smad3 is a key pathogenic factor in fibrogenesis while HIF-2α exhibits prominent renal protective effects, which is the natural substrate of von Hippel-Lindau (VHL) E3 Ligase. We hypothesied the construction of VHL-recruiting, Smad3-targeting PROTAC might combine the effects of Smad3 degradation and HIF-2α stabilization, which not only improving the clinical efficacy of PROTAC but also avoiding its potential off-target effects, could greatly improve the possibility of its translation into clinical drugs.MethodsBy joining the Smad3-binding small molecule compound (SMC) to VHL-binding SMC with a linker, we designed and synthesized a Smad3-targeting, VHL-based PROTAC. The effects of this PROTAC on targeted proteins were verified both in vitro and in vivo. The toxicity and pharmacokinetic (PK) evaluations were conducted with both male and female mice. The renal protection effects and mechanism of PROTAC were evaluated in unilateral ureteral obstruction (UUO) and 5/6 subtotal nephrectomy (5/6Nx) mouse model.ResultsBy optimizing the linker and the Smad3-binding SMC, we got a stable and high efficient PROTAC which simultaneously degraded Smad3 and stabilized HIF-2α both in vivo and in vitro. The acute toxicity evaluation showed a pretty large therapeutic window of the PROTAC. The prominent renal protection effects and its underlying mechanism including anti-fibrosis and anti-inflammatory, improving renal anemia and promoting kidney repair, had all been verified in UUO and 5/6Nx mouse model.ConclusionBy accurate combination of PROTAC targeted protein and E3 ligase, we got a Smad3-targeting, VHL-recruting PROTAC which caused Smad3 degradation and HIF-2α stabilization effects simultaneously, and led to the strong renal function protection effects.

Dataset Information

Renal tubular HIF-2? expression requires VHL inactivation and causes fibrosis and cysts.

Publications

Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets