Cardamonin retards progression of autosomal dominant polycystic kidney disease via inhibiting renal cyst growth and interstitial fibrosis

He, Jianzhong; Zhou, Hong; Meng, Jia; Zhang, Shun; Li, Xiaowei; Wang, Shuyuan; Shao, Guangying; Jin, William; Geng, Xiaoqiang; Zhu, Shuai; Yang, Baoxue

doi:10.1016/j.phrs.2020.104751

Cited by 14 publications

(20 citation statements)

References 52 publications

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“…In vivo inhibiting effects of Y6 and Y10 on renal cyst development were determined in a kidney-specific Pkd1 knockout mouse ( Pkd1 flox/flox ; Ksp-Cre , PKD) model. PKD mice develop acutely progressive ADPKD, in which renal cysts appear at postnatal day 1 and progressively enlarge, which causes death of the animal around postnatal day 14 [ 12 ]. As shown in Figure 1 G, PKD kidneys were much larger than wild-type ones.…”

Section: Resultsmentioning

confidence: 99%

“…Kidneys were collected and processed as described previously [ 12 ]. Briefly, kidneys were fixed by 4% paraformaldehyde (Sigma-Aldrich, Saint Louis, MO, USA, Cat# 158127), gradiently dehydrated by alcohol (Tong Guang, Beijing, China, Cat# 104022) and embedded in paraffin (Leica, Wetzlar, Germany, Cat# 39601095).…”

Section: Methodsmentioning

confidence: 99%

“…The advantages of low toxicity and easy availability make natural compounds ideal for ADPKD therapeutic drug development. In previous studies, we had identified several natural compounds that showed effective inhibitory effects on cyst development in ADPKD experimental models, such as curcumin [ 9 ], ginkgolide B [ 10 ], Ganoderma triterpenes [ 11 ] and cardamonin [ 12 ]. The druggabilities of these compounds are still undergoing evaluation.…”

Section: Introductionmentioning

confidence: 99%

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Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Qiu

Shao

et al. 2021

Antioxidants

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Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Qiu

Shao

et al. 2021

Antioxidants

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“…Each group had six mice to ensure the reliability of statistical analysis. The homozygous mice are characterized by rapidly progressive disease, providing only a very small window for treatment of the neonates (13). GB (0, 20, 40 or 80 mg/kg) and Cur (0, 80, 160 and 320 mg/kg) were injected subcutaneously in the back of neonatal mice once a day from days 1-10 using a 1-ml insulin syringe.…”

Section: Methodsmentioning

confidence: 99%

“…Signaling pathways associated with excessive secretion of cyst fluid include those that increase the activities of cystic fibrosis transmembrane conductance regulator (CFTR), Na + -K + -ATPase and aquaporin 2 (12). Other signaling factors include TGF-β/Smad2/3 (13) and integrin-linked kinase (14), and are associated with the pathological progression of fibrosis throughout the course of ADPKD.…”

Section: Introductionmentioning

confidence: 99%

Combination of curcumin and ginkgolide B inhibits cystogenesis by regulating multiple signaling pathways

You-song

Gao²,

et al. 2021

Mol Med Rep

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PF‐06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity

Yuan

Zhang

et al. 2022

FEBS Open Bio

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Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over‐proliferation of cyst‐lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate‐activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF‐06409577, an AMPK activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF‐06409577 effectively down‐regulated mammalian target of rapamycin pathway‐mediated proliferation of cyst‐lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator‐regulated cystic fluid secretion. Overall, our data suggest that PF‐06409577 holds therapeutic potential for ADPKD treatment.

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Cardamonin retards progression of autosomal dominant polycystic kidney disease via inhibiting renal cyst growth and interstitial fibrosis

Cited by 14 publications

References 52 publications

Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Combination of curcumin and ginkgolide B inhibits cystogenesis by regulating multiple signaling pathways

PF‐06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity

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