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Melanin-like nanoparticles slow cyst growth in ADPKD by dual inhibition of oxidative stress and CREB

ABSTRACT: Melanin-like nanoparticles (MNPs) have emerged as valuable agents in antioxidant therapy due to their excellent biocompatibility and potent ability to scavenge reactive oxygen species (ROS). However, their potential in chronic conditions remains underexplored. This study synthesized ultra-small polyethylene glycol-incorporated Mn2+-chelated MNPs (MMPP) and found that MMPP crosses the glomerular filtration barrier and accumulates specifically in renal tubules. Autosomal dominant polycystic kidney disease (ADPKD), a chronic genetic disorder associated with increased oxidative stress and progressive cyst enlargement in renal tubules, was treated with MMPP. MMPP significantly reduced oxidative stress, inhibited cyst growth, and improved renal function. Moreover, MMPP was shown to inhibit a cyst-promoting gene program downstream of the cAMP-CREB pathway, crucial in ADPKD progression. Mechanistically, MMPP directly binds to the bZIP DNA-binding domain of CREB, competitively inhibiting CREB's DNA binding and reducing its target gene expression. In summary, MMPP targets both oxidative stress and CREB transcriptional activity, demonstrating its potential for treating ADPKD.

SUBMITTER: Lirong Zhang

PROVIDER: S-SCDT-10_1038-S44321-024-00167-2 | biostudies-other |

REPOSITORIES: biostudies-other

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Dual inhibition of oxidative stress and CREB transcription activity by melanin-like nanoparticles slows cyst growth in autosomal dominant polycystic kidney disease

Project description: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 discovered 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. Furthermore, by engineering an orally administrable formulation, we demonstrated that orally delivered-MMPP also effectively inhibits cyst growth. In summary, our findings highlight the potential of MMPP in delaying the progression of ADPKD by simultaneously targeting oxidative stress and CREB transcriptional activity.

2024-10-10 | GSE235269 | GEO

Dual inhibition of oxidative stress and CREB transcription activity by melanin-like nanoparticles slows cyst growth in autosomal dominant polycystic kidney disease

Project description:Dual inhibition of oxidative stress and CREB transcription activity by melanin-like nanoparticles slows cyst growth in autosomal dominant polycystic kidney disease

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