Potential new target for diabetic kidney disease

On the cover: Immunofluorescence staining of Nox5 (red) and SM22-α (green) on human kidney biopsy obtained from an individual with diabetes showing colocalization of Nox5 (yellow) in the vascular smooth muscle cells including glomerular mesangial cells (magnification ×20). Image courtesy of Jay C. Jha, whose article, “NADPH Oxidase Nox5 Accelerates Renal Injury in Diabetic Nephropathy,” appears in this issue of Diabetes (p. 2691).

by Anne Crawford

Researchers from Monash University’s new Department of Diabetes have shed light on a protein that may play an important role in promoting diabetic kidney disease.

In a study published in the journal ‘Diabetes’ this month, Professor Karin Jandeleit-Dahm and her team found that Nox5, a pro-oxidant enzyme, was highly upregulated in human kidneys affected by diabetes.
The finding builds on work by the researchers into the NOX family (NADPH oxidases) and their role in diabetic complications, which has led to a national clinical trial of a drug to potentially treat type 1 diabetes.

The Nox inhibitor, a compound produced by the biopharmaceutical company Genkyotex Inc, Switzerland, acts mainly on the Nox1 and Nox4 isoforms of NADPH-oxidase.

Professor Jandeleit-Dahm and Dr Jay Jha led a team that produced the preclinical data on this compound, which alleviates oxidative stress, inflammation and fibrosis in the kidney in diabetic mice. Recruitment of patients with early-stage kidney disease in type1 diabetes using this drug on top of standard treatment of care has recently begun.

But until now there has been scant data about the role of Nox5 in animal models of diabetic nephropathy (kidney disease) because the isoform is absent in the mouse genome. The researchers instead investigated it in human kidney cells including in mesangial cells in response to high glucose.

“We were surprised by the finding when we did the relative comparison of NOX isoforms and found that Nox5 was predominant among them in response to diabetic stimuli,” first author Dr Jha said. “This is adding a new chapter to the NOX pathobiology,” he said.

Professor Karin Jandeleit-Dahm (centre), Dr Jay Jha (far right) &
her group, a number of whom are co-authors on the Nox5 paper.

“Diabetes is an epidemic and we will have to deal more and more with diabetic complications including diabetic nephropathy, the major cause of end-stage kidney failure requiring dialysis and transplantation, increasing deaths and also increased complications such as heart attacks, stroke and amputations,” he said.

Professor Jandeleit-Dahm said the finding had the potential to change the treatment of diabetes and its complications in the future by adding a benefit on top of other established treatments and by providing a better and more effective treatment for diabetic nephropathy and other diabetic complications.

“The finding is highly significant because it shows that we have to consider Nox5 in the context of diabetic nephropathy and that the development of novel Nox5 specific inhibitors needs to take that into account,” she said. “If we can prevent diabetic nephropathy at the early stages people will live longer and healthier lives.”

The research into Nox5 will now investigate the role of Nox5 in other diabetic complications as well as in another animal model developed to have a Nox5 gene knockout as a proof of principle study.

Reference

Jha JC, Banal C, Okabe J, Gray SP, Hettige T, Chow BSM, Thallas-Bonke V, De Vos L, Holterman CE, Coughlan MT, Power DA, Skene A, Ekinci EI, Cooper ME, Touyz RM, Kennedy CR, Jandeleit-Dahm K. NADPH Oxidase Nox5 Accelerates Renal Injury in Diabetic Nephropathy. Diabetes. 2017 Oct;66(10):2691-2703. doi: 10.2337/db16-1585. Epub 2017 Jul 26.