scholarly journals Suppressing angiotensinogen synthesis attenuates kidney cyst formation in a Pkd1 mouse model

2015 ◽  
Vol 30 (1) ◽  
pp. 370-379 ◽  
Author(s):  
Takamitsu Saigusa ◽  
Yujing Dang ◽  
Adam E. Mullick ◽  
Steve T. Yeh ◽  
Michael R. Zile ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cyst Formation ◽  
Kidney Cyst

scholarly journals Ginkgolide B inhibits renal cyst development in in vitro and in vivo cyst models

2012 ◽  
Vol 302 (10) ◽  
pp. F1234-F1242 ◽  
Author(s):  
Hong Zhou ◽  
Jinsheng Gao ◽  
Li Zhou ◽  
Xin Li ◽  
Weidong Li ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cell Viability ◽  
Intracellular Signaling ◽  
Renal Cyst ◽  
Cyst Formation ◽  
Mapk Signaling ◽  
Ginkgolide B ◽  
Inherited Disease ◽  
Kidney Cyst ◽  
Cyst Development

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.

scholarly journals A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1

2007 ◽  
Vol 13 (12) ◽  
pp. 1490-1495 ◽  
Author(s):  
Klaus Piontek ◽  
Luis F Menezes ◽  
Miguel A Garcia-Gonzalez ◽  
David L Huso ◽  
Gregory G Germino
Keyword(s):  
Cyst Formation ◽  
Kidney Cyst ◽  
Kinetics Of ◽  
Developmental Switch

scholarly journals Attenuation of accelerated renal cystogenesis in Pkd1 mice by renin-angiotensin system blockade

2018 ◽  
Vol 314 (2) ◽  
pp. F210-F218 ◽  
Author(s):  
Wayne R. Fitzgibbon ◽  
Yujing Dang ◽  
Marlene A. Bunni ◽  
Catalin F. Baicu ◽  
Michael R. Zile ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Renin Angiotensin System ◽  
Cyst Formation ◽  
Unilateral Nephrectomy ◽  
Cystic Kidney ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Kidney Cyst ◽  
Kidney Cysts

The intrarenal renin angiotensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkd1 mouse that Gen 2 antisense oligonucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared with lisinopril. The aim of this current study was to determine 1) if unilateral nephrectomy accelerates cystogenesis in Pkd1 mice (as previously shown in cilia knockout mice) and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model. Adult Pkd1 conditional floxed allele mice expressing cre were administered tamoxifen, resulting in global knockout of Pkd1. Three weeks after tamoxifen injection, mice underwent left unilateral nephrectomy. Mice were then treated with Agt ASO (75 mg/kg per week) or aliskiren (20 mg/kg per day)+Agt ASO or control for 8 wk. Unilateral nephrectomy accelerated kidney cyst formation compared with nonnephrectomized mice. Both Agt ASO and Aliskiren+Agt ASO treatments significantly reduced plasma and urinary Agt levels. Blood pressure was lowest in Aliskiren+Agt ASO mice among all treatment groups, and the control group had the highest blood pressure. All mice developed significant kidney cysts at 8 wk after nephrectomy, but Agt ASO and Aliskiren+Agt ASO groups had fewer kidney cysts than controls. Renal pAkt, pS6 levels, and apoptosis were significantly suppressed in those receiving Agt ASO compared with controls. These results indicate that suppressing Agt using an ASO slowed the progression of accelerated cystic kidney disease induced by unilateral nephrectomy in Pkd1 mice by suppressing intrarenal RAS, mammalian target of rapamycin pathway, and cell proliferation.

scholarly journals PI3K-C2α regulates Polycystin-2 ciliary entry to prevent kidney cyst formation

Cilia ◽  
2015 ◽  
Vol 4 (S1) ◽  
Author(s):  
JP Margaria ◽  
I Franco ◽  
A Ranghino ◽  
D Monteyne ◽  
M Chiaravalli ◽  
...  
Keyword(s):  
Cyst Formation ◽  
Kidney Cyst

scholarly journals Cux1 promotes cell proliferation and polycystic kidney disease progression in an ADPKD mouse model

2017 ◽  
Vol 313 (4) ◽  
pp. F1050-F1059 ◽  
Author(s):  
Binu Porath ◽  
Safia Livingston ◽  
Erica L. Andres ◽  
Alexandra M. Petrie ◽  
Joshua C. Wright ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Kidney Development ◽  
Kinase Inhibitor ◽  
Regulatory Gene ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Collecting Ducts

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1CD;Cux1tm2Ejn). While kidneys isolated from newborn Pkd1CD mice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1CD;Cux1tm2Ejn−/− mice did not show any cysts. Because Cux1tm2Ejn−/− are perinatal lethal, we evaluated Pkd1CD mice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1CD;Cux1tm2Ejn−/− mice, newborn Pkd1CD;Cux1tm2Ejn+/− mice did not show any cysts. Comparison of Pkd1CD and Pkd1CD;Cux1tm2Ejn+/− mice at later stages of development showed a reduction in the severity of PKD in the Pkd1CD;Cux1tm2Ejn+/− mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.

scholarly journals Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

2015 ◽  
Vol 27 (4) ◽  
pp. 1135-1144 ◽  
Author(s):  
Irene Franco ◽  
Jean Piero Margaria ◽  
Maria Chiara De Santis ◽  
Andrea Ranghino ◽  
Daniel Monteyne ◽  
...  
Keyword(s):  
Cyst Formation ◽  
Kidney Cyst ◽  
Phosphoinositide 3 Kinase

LOSS OF PRIMARY CILIA PRECEDES KIDNEY CYST FORMATION IN KIF3A KNOCKOUT MICE.

2007 ◽  
Vol 55 (1) ◽  
pp. S307
Author(s):  
V. Patel ◽  
P. Cobo ◽  
X. Shao ◽  
P. Igarashi
Keyword(s):  
Knockout Mice ◽  
Primary Cilia ◽  
Cyst Formation ◽  
Kidney Cyst

scholarly journals Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 532
Author(s):  
Jennifer Q. J. Zhang ◽  
Sayanthooran Saravanabavan ◽  
Gopala K. Rangan
Keyword(s):  
Kidney Disease ◽  
Autosomal Dominant ◽  
Cyst Formation ◽  
Ataxia Telangiectasia Mutated ◽  
Polycystic Kidney ◽  
Kidney Cyst ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD. In vitro, pharmacological ATM inhibition by AZD0156 reduced three-dimensional cyst growth in MDCK and human ADPKD cells by up to 4.4- and 4.1-fold, respectively. In contrast, the ATR inhibitor, VE-821, reduced in vitro MDCK cyst growth but caused dysplastic changes. In vivo, treatment with AZD0156 by oral gavage for 10 days reduced renal cell proliferation and increased p53 expression in Pkd1RC/RC mice (a murine genetic ortholog of ADPKD). However, the progression of cystic kidney disease in Pkd1RC/RC mice was not altered by genetic ablation of ATM from birth, in either heterozygous (Pkd1RC/RC/Atm+/−) or homozygous (Pkd1RC/RC/Atm−/−) mutant mice at 3 months. In conclusion, despite short-term effects on reducing renal cell proliferation, chronic progression was not altered by reducing ATM in vivo, suggesting that this DDR kinase is dispensable for kidney cyst formation in ADPKD.

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