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Fabricating a Kidney Cortex Extracellular Matrix-Derived Hydrogel
Published on: October 13, 2018
Oxidative Stress-Responsive Chemo-Physical Deformation of Hydrogel with Pygo2 Knockdown for Prevention of Kidney
Hayeon Jo1, Kaustuv Roy1, Seungho Jeon2
1Department of IT and Energy Convergence, Korea National University of Transportation, Chungju, Republic of Korea.
Abstract:
Kidney fibrosis, also known as renal fibrosis, is a condition wherein excessive scarring and interstitial inflammation of kidney tissues produce elevated levels of reactive oxygen species (ROS) and Human Pygopus 2 (Pygo2) contributing to disease progression and severity. To prevent these conditions, a fibrotic kidney-microenvironment-responsive hydrogel (PD(diSe)/shPygo2 Hydrogel) platform is designed and fabricated for providing therapy and protecting renal function. The therapeutic hydrogel provided the necessary ROS-responsiveness via cleavage of the diselenide bonds in the presence of elevated oxidative stress promoting changes in the chemo-physical property (adhesiveness, mechanical property, and electronic resistance) of the hydrogel. This transitioned the hydrogel into a more elastic state owing to a shift in Michael addition reaction between the surface amine groups in the PD(diSe) and the oxidized quinone moieties in the matrix facilitating the monitoring process. Moreover, in the presence of ROS-induced 293T cells, the hydrogel exhibited differential electrical resistance and fluorescence compared with the 293T cells alone. Additionally, the presence of shPygo2 provides therapeutic protection to fibrotic scarring and renal function in unilateral ureteral obstruction (UUO) and adenine diet murine models by downregulating the Pygo2 and α-SMA secretion levels, along with promoting ROS scavenging through diselenide bond cleavage.
Insights
A novel hydrogel platform treats kidney fibrosis by responding to reactive oxygen species (ROS) and downregulating Pygo2. This protects renal function and reduces scarring in preclinical models.
Area of Science:
- Biomaterials Science
- Renal Medicine
- Regenerative Medicine
Background:
- Kidney fibrosis involves excessive scarring and inflammation, driven by reactive oxygen species (ROS) and Pygopus 2 (Pygo2).
- Current treatments lack targeted approaches for the fibrotic kidney microenvironment.
Purpose of the Study:
- To develop a fibrotic kidney-microenvironment-responsive hydrogel (PD(diSe)/shPygo2 Hydrogel) for therapy and renal protection.
- To investigate the hydrogel's ROS-responsiveness and therapeutic efficacy in preclinical kidney fibrosis models.
Main Methods:
- Fabrication of a ROS-responsive hydrogel utilizing diselenide bonds and Michael addition reactions.
- Incorporation of short hairpin Pygopus 2 (shPygo2) for therapeutic intervention.
- Evaluation of hydrogel chemo-physical property changes (adhesiveness, mechanical, electronic resistance) in response to ROS.
- Assessment of hydrogel performance in unilateral ureteral obstruction (UUO) and adenine diet murine models.
Main Results:
- The hydrogel exhibited ROS-responsiveness, transitioning to a more elastic state and altering electrical resistance and fluorescence.
- PD(diSe)/shPygo2 Hydrogel demonstrated therapeutic protection against fibrotic scarring and preserved renal function in murine models.
- Downregulation of Pygo2 and alpha-smooth muscle actin (α-SMA) secretion was observed, alongside ROS scavenging via diselenide bond cleavage.
Conclusions:
- The developed hydrogel platform offers a promising therapeutic strategy for kidney fibrosis.
- Its ROS-responsiveness and Pygo2 downregulation capabilities effectively mitigate renal fibrosis progression and protect kidney function.
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