Research led by the University of Bristol in the U.K. suggests blocking mineralocorticoid receptor activation could help treat diabetic kidney disease, a condition that impacts around 40% of people with diabetes.
Kidney disease disproportionately impacts people with diabetes and those with the condition are four times more likely to need dialysis or a kidney transplant than someone without diabetes.
“Renin-Angiotensin-Aldosterone System blockade with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers reduce albuminuria and the risk of end stage renal disease. However, because of aldosterone escape, use of [these medications] may not reduce aldosterone-mediated mineralocorticoid receptor stimulation,” write Matthew Butler, Consultant Senior Lecturer and MRC Clinician Scientist at the University of Bristol, and colleagues in the journal JCI Insight.
A common blood pressure medication called spironolactone that blocks mineralocorticoid receptor activation has recently been shown to be effective at treating this aspect of diabetic kidney disease, by reducing the amount of protein that enters the urine, but it can have adverse effects such as high blood potassium levels.
Butler and colleagues in the U.K., Italy, The Netherlands and the U.S., carried out the current study to more closely evaluate the mechanism of action of spironolactone in diabetic kidney disease. The research team looked at kidney biopsy samples from patients with diabetic kidney disease who were treated with spironolactone and found that it protects the kidney by helping to preserve the gel-like glycocalyx layer on the surface of blood vessels within the organ, which forms the forms the first part of the glomerular filtration barrier.
The researchers also studied rats with diabetic kidney disease and found they have increased albuminuria, glomerular albumin permeability and increased glomerular matrix metalloproteinase levels, along with glycocalyx layer damage or loss. Butler and team found that blocking mineralocorticoid receptor activation in the rats helped reduce these symptoms. They also saw similar effects in human cell lines.
Data from individuals with diabetic kidney disease treated with a mineralocorticoid receptor blocker showed reduced levels of matrix metalloproteinases and albuminuria.
“This study is really exciting for us because it confirms that blocking mineralocorticoid receptors using spironolactone preserves kidney function by acting on the glycocalyx,” commented Butler, in a press statement.
“Our next steps will be to look at repurposing drugs that target matrix metalloproteases enzymes to see if they could be of benefit in patients with kidney disease and avoid the troublesome side effects associated with mineralocorticoid receptor blockers. If we see that same level of protection using these more specific drugs, then patients will see significant benefits whilst avoiding the risks associated with high blood potassium levels.”
