An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease

Yanda, Murali K.; Liu, Qiangni; Cebotaru, Liudmila

doi:10.1152/ajprenal.00186.2017

Cited by 28 publications

(19 citation statements)

References 41 publications

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“…5. Interestingly, in a previous study, we exposed PN cells to histone deacetylase 6 (HDAC6) inhibitors, which resulted in a decrease in resting intracellular Ca 2+ [48]. Consistent with increased gradient for Ca 2+ to enter the cells, the increase in intracellular Ca 2+ induced by ATP was larger when HDAC6 was inhibited vs. untreated cells, again consistent with the movement of Ca 2+ via P2X receptors.…”

Section: Discussionsupporting

confidence: 64%

Role of calcium in adult onset polycystic kidney disease

Yanda

Liu

Cebotaru

et al. 2019

Cellular Signalling

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in genes encoding the polycystin (PC) 1 and 2 proteins. The goal of this study was to determine the role of calcium in regulating cyst growth. Stromal interaction molecule 1 (STIM1) protein expression was 15-fold higher in PC1-null proximal tubule cells (PN) than in heterozygote (PH) controls and 2-fold higher in an inducible, PC1 knockout, mouse model of ADPKD compared to a non-cystic match control. IP3 receptor protein expression was also higher in the cystic mice. Knocking down STIM1 with siRNA reduced cyst growth and lowered cAMP levels in PN cells. Fura2 measurements of intracellular Ca2+ showed a dramatic reduction in thapsigargin-stimulated release of ER Ca2+ following STIM1 silencing or application of 2-APB, consistent with altered ER Ca2+ movement; the protein expression of the Ca2+-dependent adenylyl cyclases (AC) AC3 and AC6 was up- and down-regulated, respectively. Like STIM1 knockdown, application of the calmodulin inhibitor W7 lowered cAMP levels, further indicating that STIM1 regulates AC3 via Ca2+ We conclude that the high levels of STIM1 in ADPKD cells play a role in supporting cyst growth and promoting high cAMP levels and an increased release of Ca2+ from the ER. Thus, our results provide novel therapeutic targets for treating ADPKD.

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Section: Discussionsupporting

confidence: 64%

Role of calcium in adult onset polycystic kidney disease

Yanda

Liu

Cebotaru

et al. 2019

Cellular Signalling

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“…Intracellular Ca 2+ spikes dampen the levels of cAMP by inhibiting adenylate cyclases V (AC5) and VI (AC6) and by stimulating phosphodiesterase (PDE) activity [ 2 – 4 ]. PC2 and PC1 also negatively regulate AC6 at the level of its mRNA and protein expression [ 4 , 5 ]. AC6 is important for cystic growth [ 6 ] since accumulation of excess cAMP combined with Ca 2+ restriction stimulates proliferation and cyst enlargement through several pathways, including PKA, EGFR, Src, B-Raf/Erk and mTORC1 signaling [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex

et al. 2018

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Altered glucose and lipid metabolism fuel cystic growth in polycystic kidneys, but the cause of these perturbations is unclear. Renal cysts also associate with mutations in Bicaudal C1 (Bicc1) or in its self-polymerizing sterile alpha motif (SAM). Here, we found that Bicc1 maintains normoglycemia and the expression of the gluconeogenic enzymes FBP1 and PEPCK in kidneys. A proteomic screen revealed that Bicc1 interacts with the C-Terminal to Lis-Homology domain (CTLH) complex. Since the orthologous Gid complex in S. cerevisae targets FBP1 and PEPCK for degradation, we mapped the topology among CTLH subunits and found that SAM-mediated binding controls Bicc1 protein levels, whereas Bicc1 inhibited the accumulation of several CTLH subunits. Under the conditions analyzed, Bicc1 increased FBP1 protein levels independently of the CTLH complex. Besides linking Bicc1 to cell metabolism, our findings reveal new layers of complexity in the regulation of renal gluconeogenesis compared to lower eukaryotes.

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“…HDAC6 expression and activity increases in certain cancers, neurodegenerative diseases, and in Pkd1-mutant renal epithelial cells so could play a role in cyst formation and serves as a therapeutic approach in PKD (Chun, 2017). ACY-1215 also lowered cAMP levels and protein expression of AC6 (Yanda, Liu, & Cebotaru, 2017). Moreover, Valproic acid, an inhibitor of class I HADCs (HDAC1, HDAC2, HDAC3, and HDAC8) and trichostatin A, an inhibitor of class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), suppress cyst formation in PKD models.…”

Section: Therapies Associated With Histone Deacetylasesmentioning

confidence: 99%

“…In MDCK cells and PKD1-null (PN) and heterozygous (PH) cells: Reduced HDAC6 activity and thereby downregulation of cAMP levels 2. In Pkd1fl/fl; Pax8rtTA; TetO-cre mice: Slow renal cyst growth Yanda et al (2017) Note. HDAC: histone deacetylase; PKD: polycystic kidney disease.…”

Section: Egfr Hyperactivation and Mislocalizationmentioning

confidence: 99%

Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions

Malekshahabi

Rad

Serra

et al. 2019

Journal Cellular Physiology

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Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin‐1 and polycystin‐2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in‐depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.

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An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease

Cited by 28 publications

References 41 publications

Role of calcium in adult onset polycystic kidney disease

Role of calcium in adult onset polycystic kidney disease

Role of Bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex

Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions

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