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Baoxue Yang - One of the best experts on this subject based on the ideXlab platform.
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cardamonin retards progression of autosomal dominant polyCystic Kidney disease via inhibiting renal Cyst growth and interstitial fibrosis
Pharmacological Research, 2020Co-Authors: Hong Zhou, William Jin, Jia Meng, Shun Zhang, Shuyuan Wang, Guangying Shao, Xiaoqiang Geng, Shuai Zhu, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is the most common monogenetic inherited Kidney disease characterized by renal progressive fluid-filled Cysts and interstitial fibrosis. Inhibiting renal Cyst development and interstitial fibrosis has been proven effective in delaying the progression of ADPKD. The purpose of this study was to discover effective drugs from natural products for preventing and treating ADPKD. Candidate compounds were screened from a natural product library by virtual screening. The Madin-Darby canine Kidney (MDCK) Cyst model, embryonic Kidney Cyst model, and orthologous mouse model of ADPKD were utilized to determine the pharmacological activities of the candidate compounds. Western blot and morphological analysis were used to investigate underlying mechanisms. The experimental results showed that 0.625, 2.5, and 10 μM cardamonin dose-dependently reduced formation and enlargement in MDCK Cyst model. Cardamonin also significantly attenuated renal Cyst enlargement in ex vivo mouse embryonic Kidneys and PKD mouse Kidneys. We found that cardamonin inhibited renal Cyst development and interstitial fibrosis by downregulating the MAPK, Wnt, mTOR, and transforming growth factor-β/Smad2/3 signaling pathways. Cardamonin significantly inhibits renal Cyst development and interstitial fibrosis, suggesting that cardamonin shows promise as a potential therapeutic drug for preventing and treating ADPKD.
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ganoderic acid a is the effective ingredient of ganoderma triterpenes in retarding renal Cyst development in polyCystic Kidney disease
Acta Pharmacologica Sinica, 2020Co-Authors: Jia Meng, Hong Zhou, Shuyuan Wang, Shuai Zhu, Saizhen Wang, Boyue Huang, Shuqian Lin, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal Cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal Cyst development. In the present study we identified the effective ingredient of GT in suppression of Kidney Cyst development. Using an in vitro MDCK Cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25−100 μM) significantly inhibited Cyst growth in MDCK Cyst model and embryonic Kidney Cyst model in vitro, and the inhibitory effect was reversible. In Kidney-specific Pkd1 knockout (kPKD) mice displaying severe Cystic Kidney disease, administration of GA-A (50 mg· kg −1 ·d −1 , sc) significantly attenuated renal Cyst development. In both MDCK cells and Kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.
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aquaporin 3 deficiency slows Cyst enlargement in experimental mouse models of autosomal dominant polyCystic Kidney disease
The FASEB Journal, 2019Co-Authors: Hong Zhou, Xiaoqiang Geng, Baoxue Yang, Lei Lei, Weiling Wang, Yingli JiaAbstract:Human autosomal dominant polyCystic Kidney disease (ADPKD) is characterized by bilateral renal Cysts that lead to a decline in Kidney function. Previous studies reported aquaporin (AQP)-3 expression in Cysts derived from collecting ducts in ADPKD. To study the role of AQP3 in Cyst development, we generated 2 polyCystic Kidney disease (PKD) mouse models: Kidney-specific Pkd1 knockout mice and inducible Pkd1 knockout mice, each without and with AQP3 deletion. In both models, Kidney sizes and Cyst indexes were significantly reduced in AQP3-null PKD mice compared with AQP3-expressing PKD mice, with the difference seen mainly in collecting duct Cysts. AQP3-deficient Kidneys showed significantly reduced ATP content, increased phosphorylated (p)-AMPK, and decreased p-ERK and p-mammalian target of rapamycin (mTOR). In a matrix-grown Madin-Darby canine Kidney Cyst model, AQP3 expression promoted Cyst enlargement and was associated with increased expression of hypoxia-inducible factor 1-α and glucose transporter 1 and increased glucose uptake. Our data suggest that the slowed renal Cyst enlargement in AQP3 deficiency involves impaired energy metabolism in the Kidney through AMPK and mTOR signaling and impaired cellular glucose uptake. These findings implicate AQP3 as a novel determinant of renal Cyst enlargement and hence a potential drug target in ADPKD.-Wang, W., Geng, X., Lei, L., Jia, Y., Li, Y., Zhou, H., Verkman, A. S., Yang, B. Aquaporin-3 deficiency slows Cyst enlargement in experimental mouse models of autosomal dominant polyCystic Kidney disease.
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o19 ganoderma triterpenes inhibit Kidney Cyst development via down regulating the ras mapk signaling pathway
Biochemical Pharmacology, 2017Co-Authors: Ruoyun Chen, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is a common monogenetic disease characterized by progressive development of renal Cysts that leads to end stage renal disease. The aim of this study was to investigate the effect of Ganoderma triterpenes (GT), extracts from the natural product Ganoderma lucidum , on the development of Kidney Cysts. Our study revealed that GT significantly inhibited Cyst growth in a dose-dependent manner in an in vitro Cystogenesis model and an embryonic Kidney Cyst model. More importantly, GT was shown to attenuate the progression of Cyst and reduce Kidney mass in two ADPKD mouse models. To understand the underlying Cyst-inhibiting mechanism of GT, a tubulogenesis assay was performed and showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signalling pathways that are involved in the pathogenesis of PKD was further investigated by immunoblotting. Our data revealed that GT specifically downregulated forskolin-induced activation of the Ras/MAPK signalling pathways in MDCK cells without a detectable effect on the mTOR pathway. We further screened 15 monomers that were purified from GT for their effects on inhibiting Cyst formation in vitro . We demonstrated that CBLZ-7 (ethyl ganoderate C 2 ) had a potent inhibitory effect on Cyst formation in vitro . In addition, like GT, CBLZ-7 was able to downregulate FSK induced activation of the Ras/MAPK pathway. Therefore, our study demonstrated that GT and its purified monomer, CBLZ-7, are potential therapeutic regents for treating Cystic Kidney diseases.
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ginkgolide b inhibits renal Cyst development in in vitro and in vivo Cyst models
American Journal of Physiology-renal Physiology, 2012Co-Authors: Hong Zhou, Jinsheng Gao, Li Zhou, Yin Xia, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is a common inherited disease characterized by massive enlargement of fluid-filled Cysts in the Kidney. However, there is no effective therapy yet for this disease. To examine whether ginkgolide B, a natural compound, inhibits Cyst development, a Madin-Darby canine Kidney (MDCK) Cyst model, an embryonic Kidney Cyst model, and a PKD mouse model were used. Interestingly, ginkgolide B significantly inhibited MDCK Cyst formation dose dependently, with up to 69% reduction by 2 μM ginkgolide B. Ginkgolide B also significantly inhibited Cyst enlargement in the MDCK Cyst model, embryonic Kidney Cyst model, and PKD mouse model. To determine the underlying mechanisms, the effect of ginkgolide B on MDCK cell viability, proliferation, apoptosis, chloride transporter CFTR activity, and intracellular signaling pathways were also studied. Ginkgolide B did not affect cell viability, proliferation, and expression and activity of the chloride transporter CFTR that mediates Cyst fluid secretion. Ginkgolide B induced Cyst cell differentiation and altered the Ras/MAPK signaling pathway. Taken together, our results demonstrate that ginkgolide B inhibits renal Cyst formation and enlargement, suggesting that ginkgolide B might be developed into a novel candidate drug for ADPKD.
Karl Kunzelmann - One of the best experts on this subject based on the ideXlab platform.
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anoctamin 1 induces calcium activated chloride secretion and proliferation of renal Cyst forming epithelial cells
Kidney International, 2014Co-Authors: Bjoern Buchholz, Rainer Schreiber, Diana Faria, Gunnar Schley, Kai-uwe Eckardt, Karl KunzelmannAbstract:PolyCystic Kidney diseases are characterized by multiple bilateral renal Cysts that gradually enlarge and lead to a decline in renal function. Cyst enlargement is driven by transepithelial chloride secretion, stimulated by enhanced levels of cyclic adenosine monophosphate, which activates apical Cystic fibrosis transmembrane conductance regulator chloride channels. However, chloride secretion by calcium-dependent chloride channels, activated through stimulation of purinergic receptors, also has a major impact. To identify the molecular basis of calcium-dependent chloride secretion in Cyst expansion, we determined the role of anoctamin 1 and 6, two recently discovered calcium-activated chloride channels both of which are expressed in epithelial cells. We found that anoctamin 1, which plays a role in epithelial fluid secretion and proliferation, is strongly expressed in principal-like MDCK cells (PLCs) forming Cysts within a collagen matrix, in an embryonic Kidney Cyst model, and in human autosomal dominant polyCystic Kidney disease tissue. Knockdown of anoctamin 1 but not anoctamin 6 strongly diminished the calcium-dependent chloride secretion of PLCs. Moreover, two inhibitors of anoctamin ion channels, tannic acid and a more selective inhibitor of anoctamin 1, significantly inhibited PLC Cyst growth and Cyst enlargement in an embryonic Kidney Cyst model. Knockdown of ANO1 by morpholino analogs also attenuated embryonic Cyst growth. Thus, calcium-activated chloride secretion by anoctamin 1 appears to be a crucial component of renal Cyst growth.
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hypoxia inducible factor 1α causes renal Cyst expansion through calcium activated chloride secretion
Journal of The American Society of Nephrology, 2014Co-Authors: Bjoern Buchholz, Rainer Schreiber, Diana Faria, Gunnar Schley, Sven Kroening, Carsten Willam, Bernd Klanke, Nicolai Burzlaff, Jonathan Jantsch, Karl KunzelmannAbstract:PolyCystic Kidney diseases are characterized by numerous bilateral renal Cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in Kidney function over time. We previously showed that Cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1 α (HIF-1 α ) in the Cyst epithelium. Here we demonstrate a correlation between Cyst size and the expression of the HIF-1 α –target gene, glucose transporter 1, and report that HIF-1 α promotes renal Cyst growth in two in vitro Cyst models—principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse Kidneys stimulated with forskolin. In both models, augmenting HIF-1 α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced Cyst growth. In addition, inhibition of HIF-1 α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased Cyst size in the embryonic Kidney Cyst model. In contrast, inhibition of HIF-1 α by chetomin and knockdown of HIF-1 α both decreased Cyst growth in these models. Consistent with previous reports, plMDCK Cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1 α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal Cysts contributes to Cyst growth, primarily due to HIF-1 α –dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of Cyst growth.
Hong Zhou - One of the best experts on this subject based on the ideXlab platform.
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cardamonin retards progression of autosomal dominant polyCystic Kidney disease via inhibiting renal Cyst growth and interstitial fibrosis
Pharmacological Research, 2020Co-Authors: Hong Zhou, William Jin, Jia Meng, Shun Zhang, Shuyuan Wang, Guangying Shao, Xiaoqiang Geng, Shuai Zhu, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is the most common monogenetic inherited Kidney disease characterized by renal progressive fluid-filled Cysts and interstitial fibrosis. Inhibiting renal Cyst development and interstitial fibrosis has been proven effective in delaying the progression of ADPKD. The purpose of this study was to discover effective drugs from natural products for preventing and treating ADPKD. Candidate compounds were screened from a natural product library by virtual screening. The Madin-Darby canine Kidney (MDCK) Cyst model, embryonic Kidney Cyst model, and orthologous mouse model of ADPKD were utilized to determine the pharmacological activities of the candidate compounds. Western blot and morphological analysis were used to investigate underlying mechanisms. The experimental results showed that 0.625, 2.5, and 10 μM cardamonin dose-dependently reduced formation and enlargement in MDCK Cyst model. Cardamonin also significantly attenuated renal Cyst enlargement in ex vivo mouse embryonic Kidneys and PKD mouse Kidneys. We found that cardamonin inhibited renal Cyst development and interstitial fibrosis by downregulating the MAPK, Wnt, mTOR, and transforming growth factor-β/Smad2/3 signaling pathways. Cardamonin significantly inhibits renal Cyst development and interstitial fibrosis, suggesting that cardamonin shows promise as a potential therapeutic drug for preventing and treating ADPKD.
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ganoderic acid a is the effective ingredient of ganoderma triterpenes in retarding renal Cyst development in polyCystic Kidney disease
Acta Pharmacologica Sinica, 2020Co-Authors: Jia Meng, Hong Zhou, Shuyuan Wang, Shuai Zhu, Saizhen Wang, Boyue Huang, Shuqian Lin, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal Cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal Cyst development. In the present study we identified the effective ingredient of GT in suppression of Kidney Cyst development. Using an in vitro MDCK Cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25−100 μM) significantly inhibited Cyst growth in MDCK Cyst model and embryonic Kidney Cyst model in vitro, and the inhibitory effect was reversible. In Kidney-specific Pkd1 knockout (kPKD) mice displaying severe Cystic Kidney disease, administration of GA-A (50 mg· kg −1 ·d −1 , sc) significantly attenuated renal Cyst development. In both MDCK cells and Kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.
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aquaporin 3 deficiency slows Cyst enlargement in experimental mouse models of autosomal dominant polyCystic Kidney disease
The FASEB Journal, 2019Co-Authors: Hong Zhou, Xiaoqiang Geng, Baoxue Yang, Lei Lei, Weiling Wang, Yingli JiaAbstract:Human autosomal dominant polyCystic Kidney disease (ADPKD) is characterized by bilateral renal Cysts that lead to a decline in Kidney function. Previous studies reported aquaporin (AQP)-3 expression in Cysts derived from collecting ducts in ADPKD. To study the role of AQP3 in Cyst development, we generated 2 polyCystic Kidney disease (PKD) mouse models: Kidney-specific Pkd1 knockout mice and inducible Pkd1 knockout mice, each without and with AQP3 deletion. In both models, Kidney sizes and Cyst indexes were significantly reduced in AQP3-null PKD mice compared with AQP3-expressing PKD mice, with the difference seen mainly in collecting duct Cysts. AQP3-deficient Kidneys showed significantly reduced ATP content, increased phosphorylated (p)-AMPK, and decreased p-ERK and p-mammalian target of rapamycin (mTOR). In a matrix-grown Madin-Darby canine Kidney Cyst model, AQP3 expression promoted Cyst enlargement and was associated with increased expression of hypoxia-inducible factor 1-α and glucose transporter 1 and increased glucose uptake. Our data suggest that the slowed renal Cyst enlargement in AQP3 deficiency involves impaired energy metabolism in the Kidney through AMPK and mTOR signaling and impaired cellular glucose uptake. These findings implicate AQP3 as a novel determinant of renal Cyst enlargement and hence a potential drug target in ADPKD.-Wang, W., Geng, X., Lei, L., Jia, Y., Li, Y., Zhou, H., Verkman, A. S., Yang, B. Aquaporin-3 deficiency slows Cyst enlargement in experimental mouse models of autosomal dominant polyCystic Kidney disease.
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ginkgolide b inhibits renal Cyst development in in vitro and in vivo Cyst models
American Journal of Physiology-renal Physiology, 2012Co-Authors: Hong Zhou, Jinsheng Gao, Li Zhou, Yin Xia, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease (ADPKD) is a common inherited disease characterized by massive enlargement of fluid-filled Cysts in the Kidney. However, there is no effective therapy yet for this disease. To examine whether ginkgolide B, a natural compound, inhibits Cyst development, a Madin-Darby canine Kidney (MDCK) Cyst model, an embryonic Kidney Cyst model, and a PKD mouse model were used. Interestingly, ginkgolide B significantly inhibited MDCK Cyst formation dose dependently, with up to 69% reduction by 2 μM ginkgolide B. Ginkgolide B also significantly inhibited Cyst enlargement in the MDCK Cyst model, embryonic Kidney Cyst model, and PKD mouse model. To determine the underlying mechanisms, the effect of ginkgolide B on MDCK cell viability, proliferation, apoptosis, chloride transporter CFTR activity, and intracellular signaling pathways were also studied. Ginkgolide B did not affect cell viability, proliferation, and expression and activity of the chloride transporter CFTR that mediates Cyst fluid secretion. Ginkgolide B induced Cyst cell differentiation and altered the Ras/MAPK signaling pathway. Taken together, our results demonstrate that ginkgolide B inhibits renal Cyst formation and enlargement, suggesting that ginkgolide B might be developed into a novel candidate drug for ADPKD.
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curcumin inhibits renal Cyst formation and enlargement in vitro by regulating intracellular signaling pathways
European Journal of Pharmacology, 2011Co-Authors: Jinsheng Gao, Hong Zhou, Tianluo Lei, Li Zhou, Baoxue YangAbstract:Autosomal dominant polyCystic Kidney disease, a common inherited disease affecting about 1/1000 and 1/400 live births, is characterized by massive enlargement of fluid-filled Cysts and eventually causes renal failure. The purpose of this study is to identify the inhibitory effect of curcumin on renal Cyst development and to investigate the inhibitory mechanism. Madin-Darby canine Kidney (MDCK) Cyst model and murine embryonic Kidney Cyst model were used to evaluate inhibitory activity. Cell viability, proliferation, apoptosis, CFTR function and expression, and signaling pathways in MDCK cells were determined to explore the mechanism of Cyst inhibition. Curcumin was found to significantly inhibit MDCK Cyst development. At maximum dose curcumin caused 62% inhibition of the Cyst formation (IC(50) was 0.12 μM). Curcumin slowed Cyst enlargement in both MDCK Cyst model and embryonic Kidney Cyst model with dose-response relationship. Curcumin neither induced cytotoxicity nor apoptosis in MDCK cells at <100 μM. Curcumin failed to affect the chloride transporter CFTR expression and function. Interestingly, curcumin inhibited forskolin-promoted cell proliferation and promoted the tubule formation in MDCK cells, which indicates curcumin promotes MDCK cell differentiation. Furthermore, curcumin reduced the intracellular signaling proteins Ras, B-raf, p-MEK, p-ERK, c-fos, Egr-1, but increased Raf-1 and NAB2 in MDCK cells exposed to forskolin. These results define that curcumin inhibits renal Cyst formation and enlargement and suggest that curcumin might be developed as a candidate drug for polyCystic Kidney disease.
Bjoern Buchholz - One of the best experts on this subject based on the ideXlab platform.
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anoctamin 1 induces calcium activated chloride secretion and proliferation of renal Cyst forming epithelial cells
Kidney International, 2014Co-Authors: Bjoern Buchholz, Rainer Schreiber, Diana Faria, Gunnar Schley, Kai-uwe Eckardt, Karl KunzelmannAbstract:PolyCystic Kidney diseases are characterized by multiple bilateral renal Cysts that gradually enlarge and lead to a decline in renal function. Cyst enlargement is driven by transepithelial chloride secretion, stimulated by enhanced levels of cyclic adenosine monophosphate, which activates apical Cystic fibrosis transmembrane conductance regulator chloride channels. However, chloride secretion by calcium-dependent chloride channels, activated through stimulation of purinergic receptors, also has a major impact. To identify the molecular basis of calcium-dependent chloride secretion in Cyst expansion, we determined the role of anoctamin 1 and 6, two recently discovered calcium-activated chloride channels both of which are expressed in epithelial cells. We found that anoctamin 1, which plays a role in epithelial fluid secretion and proliferation, is strongly expressed in principal-like MDCK cells (PLCs) forming Cysts within a collagen matrix, in an embryonic Kidney Cyst model, and in human autosomal dominant polyCystic Kidney disease tissue. Knockdown of anoctamin 1 but not anoctamin 6 strongly diminished the calcium-dependent chloride secretion of PLCs. Moreover, two inhibitors of anoctamin ion channels, tannic acid and a more selective inhibitor of anoctamin 1, significantly inhibited PLC Cyst growth and Cyst enlargement in an embryonic Kidney Cyst model. Knockdown of ANO1 by morpholino analogs also attenuated embryonic Cyst growth. Thus, calcium-activated chloride secretion by anoctamin 1 appears to be a crucial component of renal Cyst growth.
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hypoxia inducible factor 1α causes renal Cyst expansion through calcium activated chloride secretion
Journal of The American Society of Nephrology, 2014Co-Authors: Bjoern Buchholz, Rainer Schreiber, Diana Faria, Gunnar Schley, Sven Kroening, Carsten Willam, Bernd Klanke, Nicolai Burzlaff, Jonathan Jantsch, Karl KunzelmannAbstract:PolyCystic Kidney diseases are characterized by numerous bilateral renal Cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in Kidney function over time. We previously showed that Cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1 α (HIF-1 α ) in the Cyst epithelium. Here we demonstrate a correlation between Cyst size and the expression of the HIF-1 α –target gene, glucose transporter 1, and report that HIF-1 α promotes renal Cyst growth in two in vitro Cyst models—principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse Kidneys stimulated with forskolin. In both models, augmenting HIF-1 α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced Cyst growth. In addition, inhibition of HIF-1 α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased Cyst size in the embryonic Kidney Cyst model. In contrast, inhibition of HIF-1 α by chetomin and knockdown of HIF-1 α both decreased Cyst growth in these models. Consistent with previous reports, plMDCK Cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1 α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal Cysts contributes to Cyst growth, primarily due to HIF-1 α –dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of Cyst growth.
Gunnar Schley - One of the best experts on this subject based on the ideXlab platform.
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anoctamin 1 induces calcium activated chloride secretion and proliferation of renal Cyst forming epithelial cells
Kidney International, 2014Co-Authors: Bjoern Buchholz, Rainer Schreiber, Diana Faria, Gunnar Schley, Kai-uwe Eckardt, Karl KunzelmannAbstract:PolyCystic Kidney diseases are characterized by multiple bilateral renal Cysts that gradually enlarge and lead to a decline in renal function. Cyst enlargement is driven by transepithelial chloride secretion, stimulated by enhanced levels of cyclic adenosine monophosphate, which activates apical Cystic fibrosis transmembrane conductance regulator chloride channels. However, chloride secretion by calcium-dependent chloride channels, activated through stimulation of purinergic receptors, also has a major impact. To identify the molecular basis of calcium-dependent chloride secretion in Cyst expansion, we determined the role of anoctamin 1 and 6, two recently discovered calcium-activated chloride channels both of which are expressed in epithelial cells. We found that anoctamin 1, which plays a role in epithelial fluid secretion and proliferation, is strongly expressed in principal-like MDCK cells (PLCs) forming Cysts within a collagen matrix, in an embryonic Kidney Cyst model, and in human autosomal dominant polyCystic Kidney disease tissue. Knockdown of anoctamin 1 but not anoctamin 6 strongly diminished the calcium-dependent chloride secretion of PLCs. Moreover, two inhibitors of anoctamin ion channels, tannic acid and a more selective inhibitor of anoctamin 1, significantly inhibited PLC Cyst growth and Cyst enlargement in an embryonic Kidney Cyst model. Knockdown of ANO1 by morpholino analogs also attenuated embryonic Cyst growth. Thus, calcium-activated chloride secretion by anoctamin 1 appears to be a crucial component of renal Cyst growth.
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hypoxia inducible factor 1α causes renal Cyst expansion through calcium activated chloride secretion
Journal of The American Society of Nephrology, 2014Co-Authors: Bjoern Buchholz, Rainer Schreiber, Diana Faria, Gunnar Schley, Sven Kroening, Carsten Willam, Bernd Klanke, Nicolai Burzlaff, Jonathan Jantsch, Karl KunzelmannAbstract:PolyCystic Kidney diseases are characterized by numerous bilateral renal Cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in Kidney function over time. We previously showed that Cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1 α (HIF-1 α ) in the Cyst epithelium. Here we demonstrate a correlation between Cyst size and the expression of the HIF-1 α –target gene, glucose transporter 1, and report that HIF-1 α promotes renal Cyst growth in two in vitro Cyst models—principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse Kidneys stimulated with forskolin. In both models, augmenting HIF-1 α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced Cyst growth. In addition, inhibition of HIF-1 α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased Cyst size in the embryonic Kidney Cyst model. In contrast, inhibition of HIF-1 α by chetomin and knockdown of HIF-1 α both decreased Cyst growth in these models. Consistent with previous reports, plMDCK Cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1 α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal Cysts contributes to Cyst growth, primarily due to HIF-1 α –dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of Cyst growth.
