Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease
Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5′ AMP-activated protein kinase (AMPK) inhibits cys...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4328 |
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| author | Kanlayanee Tonum Nipitpon Srimai Napason Chabang Somsak Fongsupa Patoomratana Tuchinda Jacob A. Torres Thomas Weimbs Sunhapas Soodvilai |
| author_facet | Kanlayanee Tonum Nipitpon Srimai Napason Chabang Somsak Fongsupa Patoomratana Tuchinda Jacob A. Torres Thomas Weimbs Sunhapas Soodvilai |
| author_sort | Kanlayanee Tonum |
| collection | DOAJ |
| description | Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5′ AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance regulator (CFTR)–mediated chloride secretion, leading to reduced progression of PKD. Here we investigated the pharmacological effects of panduratin A, a bioactive compound known as an AMPK activator, on CFTR-mediated chloride secretion and renal cyst development using in vitro and animal models of PKD. We demonstrated that AMPK was activated in immortalized normal renal cells and autosomal dominant polycystic kidney disease (ADPKD) cells following treatment with panduratin A. Treatment with panduratin A reduced the number of renal cyst colonies corresponding with a decrease in cell proliferation and phosphorylated p70/S6K, a downstream target of mTOR signaling. Additionally, panduratin A slowed cyst expansion via inhibition of the protein expression and transport function of CFTR. In heterozygous Han:Sprague–Dawley (Cy/+) rats, an animal model of PKD, intraperitoneal administration of panduratin A (25 mg/kg BW) for 5 weeks significantly decreased the kidney weight per body weight ratios and the cystic index. Panduratin A also reduced collagen deposition in renal tissue. Intraperitoneal administration of panduratin A caused abdominal bleeding and reduced body weight. However, 25 mg/kg BW of panduratin A via oral administration in the PCK rats, another non-orthologous PKD model, showed a significant decrease in the cystic index without severe adverse effects, indicating that the route of administration is critical in preventing adverse effects while still slowing disease progression. These findings reveal that panduratin A might hold therapeutic properties for the treatment of PKD. |
| first_indexed | 2024-03-09T10:34:06Z |
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| language | English |
| last_indexed | 2024-03-09T10:34:06Z |
| publishDate | 2022-04-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-691b688d834847e3b9917f800d8ae2092023-12-01T21:04:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238432810.3390/ijms23084328Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney DiseaseKanlayanee Tonum0Nipitpon Srimai1Napason Chabang2Somsak Fongsupa3Patoomratana Tuchinda4Jacob A. Torres5Thomas Weimbs6Sunhapas Soodvilai7Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandResearch Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandSchool of Bioinnovation and Bio-Based Product Intelligence, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandDepartment of Medical Technology, Faculty of Allied Health Science, Thammasat University Rangsit Campus, Pathumthani 12121, ThailandExcellent Center for Drug Discovery, Mahidol University, Ratchathewi, Bangkok 10400, ThailandMolecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9625, USAMolecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9625, USAResearch Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandRenal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5′ AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance regulator (CFTR)–mediated chloride secretion, leading to reduced progression of PKD. Here we investigated the pharmacological effects of panduratin A, a bioactive compound known as an AMPK activator, on CFTR-mediated chloride secretion and renal cyst development using in vitro and animal models of PKD. We demonstrated that AMPK was activated in immortalized normal renal cells and autosomal dominant polycystic kidney disease (ADPKD) cells following treatment with panduratin A. Treatment with panduratin A reduced the number of renal cyst colonies corresponding with a decrease in cell proliferation and phosphorylated p70/S6K, a downstream target of mTOR signaling. Additionally, panduratin A slowed cyst expansion via inhibition of the protein expression and transport function of CFTR. In heterozygous Han:Sprague–Dawley (Cy/+) rats, an animal model of PKD, intraperitoneal administration of panduratin A (25 mg/kg BW) for 5 weeks significantly decreased the kidney weight per body weight ratios and the cystic index. Panduratin A also reduced collagen deposition in renal tissue. Intraperitoneal administration of panduratin A caused abdominal bleeding and reduced body weight. However, 25 mg/kg BW of panduratin A via oral administration in the PCK rats, another non-orthologous PKD model, showed a significant decrease in the cystic index without severe adverse effects, indicating that the route of administration is critical in preventing adverse effects while still slowing disease progression. These findings reveal that panduratin A might hold therapeutic properties for the treatment of PKD.https://www.mdpi.com/1422-0067/23/8/4328ADPKDcystogenesisAMP-activated protein kinase (AMPK)cell proliferationcystic fibrosis transmembrane conductance regulator (CFTR)renal fluid secretion |
| spellingShingle | Kanlayanee Tonum Nipitpon Srimai Napason Chabang Somsak Fongsupa Patoomratana Tuchinda Jacob A. Torres Thomas Weimbs Sunhapas Soodvilai Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease International Journal of Molecular Sciences ADPKD cystogenesis AMP-activated protein kinase (AMPK) cell proliferation cystic fibrosis transmembrane conductance regulator (CFTR) renal fluid secretion |
| title | Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease |
| title_full | Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease |
| title_fullStr | Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease |
| title_full_unstemmed | Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease |
| title_short | Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease |
| title_sort | pharmacological effects of panduratin a on renal cyst development in in vitro and in vivo models of polycystic kidney disease |
| topic | ADPKD cystogenesis AMP-activated protein kinase (AMPK) cell proliferation cystic fibrosis transmembrane conductance regulator (CFTR) renal fluid secretion |
| url | https://www.mdpi.com/1422-0067/23/8/4328 |
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