Is there a link between kidney disease and the proteins released by kidney cells? And does the underlying genetic code influence this link?

In case you missed it a couple of months ago, work from the Rachel Lennon lab at the University of Manchester has been addressing these questions.

A network of extracellular proteins in kidney glomeruli // Image by Adam Byron

A network of extracellular proteins in kidney glomeruli

Despite many causes of chronic kidney disease, they all appear to involve disruption of the kidneys’ specialised filtration units, the glomeruli. A vital part of glomeruli (and all tissues of the body) is the extracellular matrix – the proteins released by cells to form a scaffold and communication highway for tissues. In glomeruli, these proteins form a barrier that separates the blood from what will become the urine. (For more background on the importance of the extracellular matrix in kidney function, see a previous post.)

When this extracellular barrier breaks down in kidney disease, symptoms include proteinuria, the appearance of large amounts of protein in the urine. A person’s genetic background can affect the level of proteinuria, so do genetics influence the make-up of the extracellular matrix of the kidneys?

In work published in the Journal of the American Society of Nephrology (open access), this link between genetics and the production of extracellular matrix in glomeruli was examined.

As a starting point, the expression of genes that code for the production of extracellular matrix proteins in glomeruli was compared between mice of different genetic backgrounds (see image, below). The mice were chosen because they were known to be susceptible or more resistant to kidney injury depending on their underlying genetic code. The results showed that genetic background influences the production of extracellular matrix in the glomeruli of the kidneys.

Analysis of the expression of extracellular genes by hierarchical clustering // Reproduced with permission of the American Society of Nephrology, from Randles et al. (2015) Journal of the American Society of Nephrology 26, 3021–3034 // Adaptation by Adam Byron

Analysis of the expression of extracellular genes by hierarchical clustering

Using an approach known as proteomics to analyse most or all of the proteins in a sample, glomeruli isolated from the genetically different mice were analysed. The levels of 115 extracellular proteins were measured. These results confirmed that production of some extracellular proteins depends on genetic background.

Extracellular proteins produced at different levels in kidneys that are more susceptible to injury may play a role in the pathology of kidney disease.

This work paves the way for better understanding human kidney disease.

To see if the changes in make-up of the extracellular matrix altered the structure of the glomeruli, powerful electron microscopy was used to look for defects in the extracellular barrier. Kidneys more susceptible to injury were found to have weakened or split barriers. This will contribute to symptoms of proteinuria and malfunctioning kidneys.

In this work, mice were used to understand better the features of kidney injury. Knowledge of their genetics and disease susceptibility enabled the link to extracellular matrix to be tested. But most of the extracellular proteins studied are also present in humans, and so this work paves the way for better understanding the relevance of these proteins in human kidney disease.

The altered extracellular proteins, identified in this study through links to genetics, could be future targets for drugs to fix broken barriers in the glomeruli of diseased kidneys.

Funding
This work was supported by the Wellcome Trust, Kids Kidney Research, Kidney Research UK, the MRC, the BBSRC and the University of Manchester.

Citation
Randles et al. Genetic background is a key determinant of glomerular extracellular matrix composition and organisation. J. Am. Soc. Nephrol. 26, 3021–3034 (2015)
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