Oxidative Stress-Responsive Chemo-Physical Deformation of Hydrogel with Pygo2 Knockdown for Prevention of Kidney Fibrosis.

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.