A newly developed model of kidney filtration may help researchers better understand kidney diseases such as Alport syndrome and could also be useful for drug screening efforts, a study suggests.
The study, “A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier,” was recently published in the journal Nature Communications.
Glomeruli are cellular structures in the kidney that filter the blood. Their job is essentially to remove waste from the blood to be disposed of in urine, while not removing important proteins and the like.
Because of this important role, it is vital for researchers to understand just how glomeruli function, but it’s difficult to model all the intricacies of cellular interactions within the body using just some cells in a dish.
This is the idea behind microfluidics platforms, sometimes called organs-on-a-chip. Basically, these consist of a scaffold in which researchers can precisely control the flow of liquid (and important signaling molecules therein). Cells are then grafted onto these scaffolds in a 3D structure that is more similar to how they would exist in the body.
Versions of a glomerulus-on-a-chip have actually already been developed, but many of these relied on artificial membranes between different cell types — which isn’t how things work in the human body. The researchers behind the new report wanted to make a version without these artificial dividers.
They used Organoplates, a microfluidic platform made by the company MIMETAS. They grafted onto the platform two kinds of kidney cells critical for the function of the glomerulus: glomerular endothelial cells and podocytes.
They used cells derived from three different sources: Some were taken directly from human samples; some were immortalized (cells that have been reprogrammed to provide indefinitely so they can be used continuously in cultures); and some were derived from cells in amniotic fluid.
Upon thorough examination of the chips, the researchers noted that the cells were expressing the proper markers and producing the right kind of extracellular matrix, which is the network of proteins that holds cells in the body, helping give tissues their 3D structure. The chips were successfully established about 4 out of 5 times the researchers tried.
Importantly, the cells prevented the leakage of a protein called albumin but not of a type of fiber known as inulin, which mimics what human kidneys do. Furthermore, when the cells were exposed to kidney-damaging agents, kidney cell-targeting antibodies (which are produced in some autoimmune diseases), and high levels of glucose (as in diabetes), this selective filtering ability was impaired — just as it would be in humans under those same conditions.
The researchers did note that chips made using immortalized cells weren’t as good at this as those using cells more recently derived from humans, suggesting that the latter would be more suitable for these models.
They also created glomeruli-on-a-chip using cells taken from the kidneys of Alport syndrome patients. Like the models of diabetes and autoimmune disease, these had decreased selective filtering abilities, showing that this cellular model can mimic genetic kidney disease if cells with the relevant mutation are used.
No cellular model is able to perfectly mimic the complexity of the body, the researchers acknowledge, but this model may still be useful for understanding kidney health and disease; it may also serve as a platform for drug screening and discovery.
“Altogether, these data demonstrate that this system represents a unique platform to study the [development] of glomerular diseases in a manner that, differently from previously proposed works, allows to study (1) changes in 3D conformation of podocytes, endothelial cells, and [extracellular matrix],; (2) abnormalities in their function; and (3) the crosstalk among them,” the researchers wrote.
“Chips generated with diseased podocyte lines will increase our understanding of the cellular and molecular mechanisms responsible for glomerular injury and podocyte loss and will advance the design and evaluation of therapeutics strategically targeted to the glomerulus, thus ultimately benefiting patients affected by [chronic kidney disease] and renal failure,” they concluded.