Development of a Functional Glomerulus at the Organ Level on a Chip to Mimic Hypertensive Nephropathy

Abstract

Glomerular hypertension is an important factor exacerbating glomerular diseases to end-stage renal diseases because, ultimately, it results in glomerular sclerosis (especially in hypertensive and diabetic nephropathy). The precise mechanism of glomerular sclerosis caused by glomerular hypertension is unclear, due partly to the absence of suitable in vitro or in vivo models capable of mimicking and regulating the complex mechanical forces and/or organ-level disease processes. We developed a “glomerulus-on-a-chip” (GC) microfluidic device. This device reconstitutes the glomerulus with organ-level glomerular functions to create a disease model-on-a chip that mimics hypertensive nephropathy in humans. It comprises two channels lined by closely opposed layers of glomerular endothelial cells and podocytes that experience fluid flow of physiological conditions to mimic the glomerular microenvironment in vivo. Our results revealed that glomerular mechanical forces have a crucial role in cellular cytoskeletal rearrangement as well as the damage to cells and their junctions that leads to increased glomerular leakage observed in hypertensive nephropathy. Results also showed that the GC could readily and flexibly meet the demands of a renal-disease model. The GC could provide drug screening and toxicology testing, and create potential new personalized and accurate therapeutic platforms for glomerular disease.

Organ‐On‐A‐Chip Platforms: A Convergence of Advanced Materials, Cells, and Microscale Technologies

“…The most widely modeled component of the kidney is the proximal tubule . Recent development has also attempted to model the kidney glomerulus . However, there has been no attempt to combine various components of kidney into a single OOC system.…”

Nephrotic syndrome in a dish: recent developments in modeling in vitro

“…In the past decade, significant progress has been made in generating microfluidic organs-on-a-chip that basically consist of cells cultured on a 2D surface or in 3D tubular structures accompanied by controlled fluid flow throughout the system, either luminal, basal or both. Proof-of-concept studies have showed the successful engineering of a glomerulus-on-a-chip [55,66,67] (Fig. 2).…”

“…c Organoids contain multiple nephrons and glomeruli consist of podocytes, endothelial cells, glomerular basement membrane, and parietal epithelial cells, though not fully mature. d Differentiation of podocyte-like cells in 2D or e in a glomerulus-on-a-chip expression levels [66,67]. In these studies, either murine immortalized cells or human primary glomerular tissue were used.…”

Organ‐on‐a‐Chip Technology for Reproducing Multiorgan Physiology

“…The authors of this study concluded that the native ECM composition contributed to the formation of microvasculature structure. A “glomerulus‐on‐a‐chip” was developed, which comprises two channels lined by opposed layers of glomerular endothelial cells and podocytes . Authors observed that mechanical forces on the cells exerted by the chip plays a crucial role in cellular cytoskeleton rearrangement.…”