New diabetic kidney disease target raises hopes

Monash University scientists are developing what could be a promising new therapeutic target to combat diabetic kidney disease.

The Central Clinical School researchers led by Professor Karin Jandeleit-Dahm and Dr Jay Chandra Jha, together with an international collaboration, recently revealed details of the predominantly pathological role of the pro-oxidant enzyme NOX5 in diabetic complications, particularly diabetic kidney disease (DKD), and are working on small molecule inhibitors to target it.

Their study was published in the leading international journal Diabetes this month.

About 40 per cent of diabetic individuals are affected by diabetic kidney disease, which is incurable and can be fatal.

“We need to find a novel therapeutic target to combat this problem,” Dr Jha said.

Dr Jha, who conducted his PhD studies into NOX isoforms, began researching NOX5 to ascertain whether it would be a better target than the previously characterised NOX4 isoform, currently in a clinical trial led by the Monash Department of Diabetes researchers.

“This is the first proof-of concept study we have that delineated that NOX5 is superior to NOX4,” he said.

The NOX isoforms are an important source of reactive oxygen species (ROS), reactive chemicals that can damage or kill cells if they are produced excessively and accumulate in the body. Oxidative stress results in kidney damage by increasing inflammation and fibrosis ultimately leading to kidney failure.

“NOX5 is unique particularly because it is present in humans but not in conventional rodent models, which is why it was overlooked so far and could not be investigated in conventional animal models,” Dr Jha said. “We generated a transgenic mouse model introducing the human gene for NOX5 in mice and asked the question of whether expression of human NOX5 would have any impact in terms of damage to the kidneys,” he said. “We also wanted to know what is the role of NOX5 independent of NOX4.”

The scientists used both genetic and pharmacological approaches in diabetic mice and found NOX5 caused more kidney injury than NOX4. They are now validating small molecule inhibitors that specifically target NOX5 in DKD in preclinical studies and would translate the findings to the clinic as quickly as possible, he said.

“We think this is hugely important,” Professor Jandeleit-Dahm said. “There is still no cure for diabetic kidney disease. There is no real direct kidney-targeting medication for reducing oxidative stress,” she said.

“A mechanism-based approach directly targeting the source of oxidative stress in the kidney is probably more promising and is currently not sufficiently targeted by standard therapy. It would be used in combination with these.”

Jha JC, Dai  A, Garzarella  J, Charlton A, Urner  S, Østergaard  JA, Okabe  J, Holterman CE, Skene  A, Power  DA, Ekinci EI, Coughlan MT, Schmidt HHHW, Cooper  ME, Touyz  RM, Kennedy CR, Jandeleit-Dahm K. Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways. Diabetes. 2022 Jun 1;71(6):1282-1298.  doi: 10.2337/db21-1079