Faculty Opinions recommendation of Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease.

2013 ◽  
Author(s):  
Brian Blagg ◽  
Suman Ghosh
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Hsp90 Chaperone ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

scholarly journals Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease

2013 ◽  
Vol 110 (31) ◽  
pp. 12786-12791 ◽  
Author(s):  
T. Seeger-Nukpezah ◽  
D. A. Proia ◽  
B. L. Egleston ◽  
A. S. Nikonova ◽  
T. Kent ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Hsp90 Chaperone ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

scholarly journals A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease

2019 ◽  
Vol 317 (1) ◽  
pp. F187-F196 ◽  
Author(s):  
Sara J. Holditch ◽  
Carolyn N. Brown ◽  
Daniel J. Atwood ◽  
Andrew M. Lombardi ◽  
Khoa N. Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Kinase Inhibitor ◽  
Polycystic Kidney ◽  
Mtor Kinase ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. Sirolimus indirectly inhibits mTORC1. Novel mTOR kinase inhibitors directly inhibit mTOR kinase, resulting in the inhibition of mTORC1 and mTORC2. The aim of the present study was to determine the effects of sirolimus versus the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C ( Pkd1RC/RC) mouse model, a hypomorphic Pkd1 model orthologous to the human condition, and to determine the effects of sirolimus versus torin2 on mTORC1 and mTORC2 signaling in PKD1−/− cells and in the kidneys of Pkd1RC/RC mice. In vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and negatively impacted cellular metabolic activity, as measured by MTT assay. Pkd1RC/RC mice were treated with sirolimus or torin2 from 50 to 120 days of age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 protein, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1, phosphorylated Akt, and proliferation in Pkd1RC/RC kidneys. In conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden and improving kidney function and mediated comparable effects on mTORC1 and mTORC2 signaling and proliferation in the Pkd1RC/RC kidney.

Quercetin inhibits renal cyst growth in vitro and via parenteral injection in a polycystic kidney disease mouse model

2018 ◽  
Vol 9 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Yangyang Zhu ◽  
Tian Teng ◽  
Hu Wang ◽  
Hao Guo ◽  
Lei Du ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Renal Cyst ◽  
Monogenic Disease ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by massive enlargement of fluid-filled cysts in the kidney.

scholarly journals Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Ding ◽  
Linda Xiaoyan Li ◽  
Peter C. Harris ◽  
Junwei Yang ◽  
Xiaogang Li
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Extracellular Vesicles ◽  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.

HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease

2018 ◽  
Vol 94 (5) ◽  
pp. 887-899 ◽  
Author(s):  
Andre Kraus ◽  
Dorien J.M. Peters ◽  
Bernd Klanke ◽  
Alexander Weidemann ◽  
Carsten Willam ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease

2018 ◽  
Author(s):  
Albert C. M. Ong ◽  
Timothy Ellam
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Functional Decline ◽  
Renal Cysts ◽  
Common Symptom ◽  
Polycystic Kidney ◽  
Cystic Change ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (ADPKD) is responsible for up to 10% of prevalent patients with end-stage renal disease (ESRD). It is characterized by the enlargement of multiple bilateral renal cysts, present in almost all patients by their fifth decade. Loin pain is a common symptom that may be caused by cyst growth, intracyst haemorrhage, nephrolithiasis, or infection. Gross haematuria is also a common feature, but usually settles spontaneously. Excretory impairment develops after extensive cystic change has occurred and progresses to ESRD in half of all affected patients by the age of 60. However, the onset of cystic change and rate of renal functional decline are highly variable between individuals. ADPKD associated with the PKD1 gene has an earlier average age of cyst development and ESRD than PKD2, but the two cannot be distinguished on clinical grounds. Polycystins 1 and 2 are expressed in various organs and extrarenal disease may be the presenting feature. Intracranial aneurysms are five times more common in patients with ADPKD, but rupture is infrequent. Liver cysts are present in most patients and may be complicated by haemorrhage or infection, though liver failure is very rare. Massive hepatic cystic disease is confined to women, reflecting stimulatory effects of oestrogen on hepatic cyst growth. Cardiovascular disease is the leading cause of death in ADPKD and vascular dysfunction is present in many patients even before the development of excretory impairment. However, despite the multisystem manifestations of ADPKD, survival from ESRD is better for patients with ADPKD than for other non-diabetic causes of kidney failure.

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