Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor
Open accessAbstract
Unlabelled Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor.Background We have previously demonstrated an essential role for increased epidermal growth factor receptor (EGFR) activity in mediating renal cyst formation and biliary epithelial hyperplasia in murine models of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to determine whether or not treatment with a newly developed inhibitor of EGFR tyrosine kinase activity (EKI-785) would reduce renal and biliary abnormalities in murine ARPKD.Methods Balb/c-bpk/bpk (BPK) litters were treated with EKI-785, an EGFR-specific tyrosine kinase inhibitor. Animals were treated by intraperitoneal injection beginning at postnatal day 7 and were treated until postnatal day 24 or 48. EKI-785's effectiveness was measured by a reduction in the renal cystic index, an increased life span, and maintenance of normal renal function.Results Treatment of BPK mice with EKI-785 resulted in a marked reduction of collecting tubule (CT) cystic lesions, improved renal function, decreased biliary epithelial abnormalities, and an increased life span. Untreated cystic animals died of renal failure at postnatal day 24 (P-24) with a CT cystic index of 4.8, a maximal urine osmolarity of 361 mOsm, and moderate to severe biliary abnormalities. Cystic animals treated with EKI-785 to postnatal day 48 (P-48) were alive and well with normal renal function, a reduced CT cystic index of 2.0 (P < 0.02), a threefold increased in maximum urinary concentrating ability (P < 0.01), and a significant decrease in biliary epithelial proliferation/fibrosis (P < 0.01).Conclusion This study demonstrates that EKI-785 has therapeutic effectiveness in improving histopathologic abnormalities and decreasing mortality in murine ARPKD.
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CL-387785 has shown potential to overcome T790M mutation-related resistance at functional level.
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- Authors
- Sweeney, W. E., Chen, Y., Nakanishi, K., Frost, P., & Avner, E. D.
- Affiliations
- Rainbow Babies & Children's Hospital (US)
- Corresponding author
- Avner, Ellis D.
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2000-01
- Volume
- 57
- Issue
- 1
- Pages
- 33-40
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W1966120295
- Cited by
- 219
- References
- 38
- Citations by year
- 2025: 2 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 8 · 2016: 7 · 2015: 12 · 2014: 5 · 2013: 7 · 2012: 11
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk044875-02, 5r01dk051068-04)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-51068, DK44875)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Keywords
- autosomal recessive polycystic kidney disease, EGFR tyrosine kinase inhibitors, epidermal growth factor receptor, renal cyst formation, urine concentrating ability, lifespan, renal fibrosis
- MeSH terms
- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Polycystic Kidney Diseases, Mice, Inbred BALB C, Protein-Tyrosine Kinases, Quinazolines, Mice
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