Mechano-chemical Insights in Diabetic Kidney Disease through 3D Pathotypic Model of Mesangium

Abstract

ABSTRACTThe mesangium is a crucial microenvironment in the kidney. It consists of mesangial cells and extracellular matrix that lends structural integrity to the glomerulus and aids renal filtration. The mesangial cells function in a delicate balance of matrix mechanics and chemical cues to engage in matrix formation, cell interactions, and cytokine production. Irregularities such as diabetes disturb this delicate balance leading to declining kidney function and kidney failure. While chemical and molecular studies on mesangium during diabetic kidney disease (DKD) are abundant, little is known about how the changing matrix mechanics affect the mesangial function. Here we demonstrate the co-stimulatory effects of chemical cues and matrix properties within the mesangial niche afflicted with DKD. To avail control of both mechanical and chemical parameters typical of DKD, we used photo-cured gelatin methacryloyl hydrogels to emulate mesangium in different disease stages. We simulated soft and stiff matrices to mechanically match mesangium in healthy and long-term DKD with fibrosis conditions. The mechanical properties play a dominant role over chemical factors inα−smooth muscle actin formation. This coincided with a reduction in mesangial cell processes and motility, crucial for cell interactions. The fibrotic matrix also profoundly influences collagen IV expression, potentially resulting in a thickened renal basement membrane around capillaries, reducing renal filtration efficiency. The study implies that the mechano-chemical dual input in late-stage DKD causes an accelerated decline in glomerular function. The finding consolidates viable reasoning for therapeutic challenges in late-stage kidney disease and directs future studies to find the missing pieces in understanding kidney disease through such in-vitro pathotypic models.