Endogenous nitric oxide inhibitors may play a key role in protecting kidneys against chronic kidney disease, a new CSC study shows.
Chronic kidney disease affects approximately 10 per cent of the population and involves progressive scarring of the kidneys, leading to loss of function and a higher risk of heart disease and strokes. There is no cure and very few effective treatments. Nitric oxide synthase (NOS) enzymes produce nitric oxide (NO) that regulates kidney function and blood pressure. High levels of a NOS inhibitor called ADMA are associated with kidney failure because it blocks the synthesis of nitric oxide, causing high blood pressure and impaired kidney function. However, the CSC’s Nitric Oxide Signalling Group has made the surprising discovery that ADMA may actually serve to protect against progressive chronic kidney disease.
In a study published this month in the Journal of the American Society of Nephrology, the researchers confirm in mice models and kidney transplant patients that nitric oxide inhibition in specialised regions of the kidney, the proximal tubules, can protect against chronic kidney disease.
By creating a transgenic mouse with a deleted DDAH1 gene, which codes for an enzyme that metabolises ADMA, thereby reducing nitric oxide production in its proximal tubules, and subjecting it to two different kinds of kidney injury, progressive scarring and loss of function were shown to be reduced. Increased levels of proximal tubule ADMA in the DDAH1 knock-out mice also caused reduced kidney collagen and uromodulin expression – two genes that are implicated in kidney disease and under intense investigation as potential therapeutic targets. Consistent with these findings, the researchers also analysed kidney transplant patient biopsy tissue and found that those with a lower level of the DDAH enzyme had better kidney function on follow-up, confirming that kidney specific inhibition of nitric oxide synthesis can protect against progressive kidney disease.
“This finding is completely novel and goes against the dogma that loss of nitric oxide is always bad for you. This is a good example of a situation where it is actually protective,” says James Leiper, leader of the CSC’s Nitric Oxide Signalling Group. James Tomlinson, a Chain-Florey Clinical Lecturer at the CSC and lead author of the paper, adds, “In future studies, we will investigate exactly how nitric oxide regulates uromodulin and how uromodulin may protect the kidney.”
James Tomlinson says that for patients with chronic kidney failure, treatments that simply boost nitric oxide levels are likely to accelerate the decline in kidney function, whereas partially blocking nitric oxide production through DDAH1 inhibition in the kidney may prove an effective treatment for chronic kidney disease.
“This paper demonstrates the strength of combining the very strong basic science from the CSC together with clinical medicine from Imperial College and ICL NHS Trust, and may have significant implications on the management of patients with chronic kidney disease,” he adds.
Tomlinson JA, Caplin B, Boruc O, Bruce-Cobbold C, Cutillas P, Dormann D, Faull P, Grossman RC, Khadayate S, Mas VR, Nitsch DD, Wang Z, Norman JT, Wilcox CS, Wheeler DC, Leiper J (2015): Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage. J Am Soc Nephrol, pii: ASN.2014030280. [Epub ahead of print]
The CSC’s Chain-Florey Clinical Research Fellowships offer medical graduates the opportunity to complete PhDs in basic science at the CSC. Clinically trained Fellows develop a unique appreciation of the practical application of treatments and bring a valuable perspective to science research. Since the scheme’s inception in 2009, 17 Fellowships have been awarded and graduates have emerged ready to tackle clinical research questions with scientific precision. The scheme is jointly funded by the MRC and NIHR through the Imperial BRC.
The Fellowship is named in celebration of the great collaboration between Howard Florey, a clinically trained pathologist, and Ernst Chain, a biochemist, who shared the 1945 Nobel Prize in Physiology or Medicine with Alexander Fleming for their work in discovering, developing and producing the first antibiotic: penicillin.
To read more about the scheme, its sponsors and advocates, current and previous Fellows, please download the 2014 Chain Florey Fellowship brochure here.
