Calcium Ameliorates Renal Cyst Growth in Metanephric Organ Culture: A Morphological Study

Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models. However, clinical trials with mTOR inhibitors were disappointing largely due to the intolerable extrarenal side effects during long-term treatment with these drugs. Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in ADPKD patients. To overcome this problem, we previously demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and FC-rapa are similarly effective on polycystic kidneys in this model. However, FC-rapa lacks the extrarenal effects of unconjugated rapamycin, in particular immunosuppressive effects. We conclude that folate-conjugation is a promising avenue for increasing the tissue specificity of small-molecule compounds to facilitate very long-term treatment in ADPKD.

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The tyrosine-kinase inhibitor Nintedanib ameliorates autosomal-dominant polycystic kidney disease

Cell Death and Disease ◽

10.1038/s41419-021-04248-9 ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Abeda Jamadar ◽

Sreenath M. Suma ◽

Sijo Mathew ◽

Timothy A. Fields ◽

Darren P. Wallace ◽

...

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Kidney Disease ◽

Autosomal Dominant ◽

Renal Cyst ◽

Growth Factor Receptor ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Cyst Growth

AbstractAutosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by progressive growth of fluid-filled cysts. Growth factors binding to receptor tyrosine kinases (RTKs) stimulate cell proliferation and cyst growth in PKD. Nintedanib, a triple RTK inhibitor, targets the vascular endothelial growth-factor receptor (VEGFR), platelet-derived growth-factor receptor (PDGFR), and fibroblast growth-factor receptor (FGFR), and is an approved drug for the treatment of non-small-cell lung carcinoma and idiopathic lung fibrosis. To determine if RTK inhibition using nintedanib can slow ADPKD progression, we tested its effect on human ADPKD renal cyst epithelial cells and myofibroblasts in vitro, and on Pkd1f/fPkhd1Cre and Pkd1RC/RC, orthologous mouse models of ADPKD. Nintedanib significantly inhibited cell proliferation and in vitro cyst growth of human ADPKD renal cyst epithelial cells, and cell viability and migration of human ADPKD renal myofibroblasts. Consistently, nintedanib treatment significantly reduced kidney-to-body-weight ratio, renal cystic index, cystic epithelial cell proliferation, and blood-urea nitrogen levels in both the Pkd1f/fPkhd1Cre and Pkd1RC/RC mice. There was a corresponding reduction in ERK, AKT, STAT3, and mTOR activity and expression of proproliferative factors, including Yes-associated protein (YAP), c-Myc, and Cyclin D1. Nintedanib treatment significantly reduced fibrosis in Pkd1RC/RC mice, but did not affect renal fibrosis in Pkd1f/fPkhd1Cre mice. Overall, these results suggest that nintedanib may be repurposed to effectively slow cyst growth in ADPKD.

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Regression of Peritubular Capillaries Coincides with Angiogenesis and Renal Cyst Growth in Experimental Polycystic Kidney Disease

International Journal of Nephrology and Renovascular Disease ◽

10.2147/ijnrd.s238767 ◽

2020 ◽

Vol Volume 13 ◽

pp. 53-64 ◽

Cited By ~ 1

Author(s):

Kristal O'Brien ◽

Sayanthooran Saravanabavan ◽

Jennifer QJ Zhang ◽

Annette TY Wong ◽

Alexandra Munt ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Renal Cyst ◽

Polycystic Kidney ◽

Peritubular Capillaries ◽

Cyst Growth

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

Food & Function ◽

10.1039/c7fo01253e ◽

2018 ◽

Vol 9 (1) ◽

pp. 389-396 ◽

Cited By ~ 6

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.

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