Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB
Abstract Melanin-like nanoparticles (MNPs) have recently emerged as valuable agents in antioxidant therapy due to their excellent biocompatibility and potent capacity to scavenge various reactive oxygen species (ROS). However, previous studies have mainly focused on acute ROS-related diseases, leavi...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-11-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00167-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594510792622080 |
|---|---|
| author | Yongzhan Sun Quan Zou Huizheng Yu Xiaoping Yi Xudan Dou Yu Yang Zhiheng Liu Hong Yang Junya Jia Yupeng Chen Shao-Kai Sun Lirong Zhang |
| author_facet | Yongzhan Sun Quan Zou Huizheng Yu Xiaoping Yi Xudan Dou Yu Yang Zhiheng Liu Hong Yang Junya Jia Yupeng Chen Shao-Kai Sun Lirong Zhang |
| author_sort | Yongzhan Sun |
| collection | DOAJ |
| description | Abstract Melanin-like nanoparticles (MNPs) have recently emerged as valuable agents in antioxidant therapy due to their excellent biocompatibility and potent capacity to scavenge various reactive oxygen species (ROS). However, previous studies have mainly focused on acute ROS-related diseases, leaving a knowledge gap regarding their potential in chronic conditions. Furthermore, apart from their well-established antioxidant effects, it remains unclear whether MNPs target other intracellular molecular pathways. In this study, we synthesized ultra-small polyethylene glycol-incorporated Mn2+-chelated MNP (MMPP). We found that MMPP traversed the glomerular filtration barrier and specifically accumulated in renal tubules. Autosomal dominant polycystic kidney disease (ADPKD) is a chronic genetic disorder closely associated with increased oxidative stress and featured by the progressive enlargement of cysts originating from various segments of the renal tubules. Treatment with MMPP markedly attenuated oxidative stress levels, inhibited cyst growth, thereby improving renal function. Interestingly, we found that MMPP effectively inhibits a cyst-promoting gene program downstream of the cAMP-CREB pathway, a crucial signaling pathway implicated in ADPKD progression. Mechanistically, we observed that MMPP directly binds to the bZIP DNA-binding domain of CREB, leading to competitive inhibition of CREB’s DNA binding ability and subsequent reduction in CREB target gene expression. In summary, our findings identify an intracellular target of MMPP and demonstrate its potential for treating ADPKD by simultaneously targeting oxidative stress and CREB transcriptional activity. |
| format | Article |
| id | doaj-art-ccaa0b018a8c4f9c9c7cd7f40540d490 |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-ccaa0b018a8c4f9c9c7cd7f40540d4902025-01-19T12:34:42ZengSpringer NatureEMBO Molecular Medicine1757-46842024-11-0117116919210.1038/s44321-024-00167-2Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREBYongzhan Sun0Quan Zou1Huizheng Yu2Xiaoping Yi3Xudan Dou4Yu Yang5Zhiheng Liu6Hong Yang7Junya Jia8Yupeng Chen9Shao-Kai Sun10Lirong Zhang11The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Radiology, The Second Hospital of Tianjin Medical UniversityThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical UniversityThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Nephrology, Tianjin Medical University General HospitalThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversitySchool of Medical Imaging, Tianjin Medical UniversityThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityAbstract Melanin-like nanoparticles (MNPs) have recently emerged as valuable agents in antioxidant therapy due to their excellent biocompatibility and potent capacity to scavenge various reactive oxygen species (ROS). However, previous studies have mainly focused on acute ROS-related diseases, leaving a knowledge gap regarding their potential in chronic conditions. Furthermore, apart from their well-established antioxidant effects, it remains unclear whether MNPs target other intracellular molecular pathways. In this study, we synthesized ultra-small polyethylene glycol-incorporated Mn2+-chelated MNP (MMPP). We found that MMPP traversed the glomerular filtration barrier and specifically accumulated in renal tubules. Autosomal dominant polycystic kidney disease (ADPKD) is a chronic genetic disorder closely associated with increased oxidative stress and featured by the progressive enlargement of cysts originating from various segments of the renal tubules. Treatment with MMPP markedly attenuated oxidative stress levels, inhibited cyst growth, thereby improving renal function. Interestingly, we found that MMPP effectively inhibits a cyst-promoting gene program downstream of the cAMP-CREB pathway, a crucial signaling pathway implicated in ADPKD progression. Mechanistically, we observed that MMPP directly binds to the bZIP DNA-binding domain of CREB, leading to competitive inhibition of CREB’s DNA binding ability and subsequent reduction in CREB target gene expression. In summary, our findings identify an intracellular target of MMPP and demonstrate its potential for treating ADPKD by simultaneously targeting oxidative stress and CREB transcriptional activity.https://doi.org/10.1038/s44321-024-00167-2Melanin-like NanoparticleReactive Oxygen SpeciescAMP-CREB PathwayADPKD Therapy |
| spellingShingle | Yongzhan Sun Quan Zou Huizheng Yu Xiaoping Yi Xudan Dou Yu Yang Zhiheng Liu Hong Yang Junya Jia Yupeng Chen Shao-Kai Sun Lirong Zhang Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB EMBO Molecular Medicine Melanin-like Nanoparticle Reactive Oxygen Species cAMP-CREB Pathway ADPKD Therapy |
| title | Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB |
| title_full | Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB |
| title_fullStr | Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB |
| title_full_unstemmed | Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB |
| title_short | Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB |
| title_sort | melanin like nanoparticles slow cyst growth in adpkd by dual inhibition of oxidative stress and creb |
| topic | Melanin-like Nanoparticle Reactive Oxygen Species cAMP-CREB Pathway ADPKD Therapy |
| url | https://doi.org/10.1038/s44321-024-00167-2 |
| work_keys_str_mv | AT yongzhansun melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT quanzou melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT huizhengyu melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT xiaopingyi melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT xudandou melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT yuyang melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT zhihengliu melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT hongyang melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT junyajia melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT yupengchen melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT shaokaisun melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb AT lirongzhang melaninlikenanoparticlesslowcystgrowthinadpkdbydualinhibitionofoxidativestressandcreb |