Kidney research sheds light on harms of certain drugs

Washington: A new study saw scientists identify an enzyme that, if suppressed, can trigger renal failure. Their findings have implications for the use of existing drugs and the development of new pharmaceuticals.

The study, published in Nature Communications, saw a global research team, led by the University of Bristol study how the activity of the enzyme GSK3 (Glycogen Synthase Kinase 3) affects the function of podocyte cells, which are crucial in enabling the kidneys to filter blood.

In the podocyte, the GSK3 (which are of two types) enzyme stops the body from leaking protein into the urine and so prevents the development of kidney failure. However, when both GSK3 forms are excessively suppressed, they become highly detrimental both in a developing kidney and in a fully mature kidney, increasing the likelihood of renal failure. One of the drugs, available in the market, is known to suppress GKS3 in lithium.

This is commonly used as a psychiatric medication and for conditions including bipolar disease. Some patients taking this medicine for a long time, or at high doses, have been shown to leak large amounts of protein into their urine and develop kidney failure needing dialysis or a kidney transplant.

There has also been a drive from the pharmacological industry in the past to develop GSK3 inhibitors for treating diabetes, cancer and Alzheimer`s.This has prompted the authors of the paper to urge pharma companies to ensure that when developing these drugs, they ensure that the drugs do not over-suppress both forms of GSK3.

Speaking about the study, lead author Richard Coward said, “We think that patients who are taking lithium treatment now should regularly have a simple urine test to measure the amount of albumin they are excreting, as too much albumin is a sign of kidney disease.

"He added,"If these patients have increased levels of protein in their urine, they should consider reducing their dose of their lithium or switching medications. We think this could prevent some of them from developing kidney failure.”The research further suggests that it would be sensible to try and develop drugs that selectively inhibit one of the two forms of GSK3.

Earlier studies had suggested that inhibiting GSK3 in the podocyte may be beneficial in treating kidney disease. This is probably due to them selectively inhibiting this form of the enzyme. However, this latest research shows that too much suppression of the activity of this enzyme is harmful.

The study found authors studying mice and flies that had GSK3 selectively knocked out in their podocyte (or podocyte-like) cells. In both species it was highly detrimental. They also looked at the reason why the podocyte became unhealthy by studying podocyte cells in a dish.

The international team of researchers, which includes experts from the UK, Canada, USA and New Zealand, now plan to focus on a detailed understanding of the signalling pathways that GSK3 controls in the podocyte.

By working out what the different isoforms (alpha and beta) control, further insights could reveal pathways that are "good" and "bad" for the podocyte, which could be targeted in the future to treat several different kidney diseases.