NAD(P)H oxidase isoforms as therapeutic targets for diabetic complications

Abstract

The development of macro- and microvascular complications is accelerated in diabetic patients. While some therapeutic regimes have helped in delaying progression of complications, none have yet been able to halt the progression and prevent vascular disease, highlighting the need to identify new therapeutic targets. Increased oxidative stress derived from the NADPH oxidase (Nox) family has recently been identified to play an important role in the pathophysiology of vascular disease. In recent years, specific Nox isoforms have been implicated in contributing to the development of atherosclerosis of major vessels, as well as damage of the small vessels within the kidney and the eye. With the use of novel Nox inhibitors, it has been demonstrated that these complications can be attenuated, indicating that targeting Nox derived oxidative stress holds potential as a new therapeutic strategy.

Keywords::

• atherosclerosis
• cardiovascular disease
• diabetes
• NADPH oxidase
• nephropathy
• oxidative stress
• retinopathy

Financial & competing interests disclosure

This work has been supported by the NHMRC. E Di Marco has received support from the National Heart Foundation Postgraduate Scholarship. KAM Jandeleit-Dahm has received support from an NHMRC senior Research Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Cardiovascular and renal disease are accelerated in diabetes compared with nondiabetic patients.

• Experimental evidence suggests a causal association between the development of diabetes complications, including macro- and microvascular disease, and oxidative stress derived from Nox.

• There are four principal isoforms of NAD(P)H oxidase (Nox) (Nox1, Nox2, Nox4 and Nox5), which have been experimentally linked to contribute to enhanced oxidative stress and development of diabetic complications.

• Nox1 has been shown to be predominantly involved in macrovascular complications of diabetes and retinopathy of prematurity in addition to hypertension and atherosclerosis.

• Nox2 is predominantly expressed in immune cells; however, in diabetic animals, targeted global deletion of Nox2 leads to development of septicemia, indicating that Nox2 is an unfavorable target in diabetes.

• In contrast, Nox4 appears to be heavily expressed in the kidney and is further increased in disease settings, and in turn, targeted disruption of Nox4, by pharmacological and genetic approaches prevents the development of diabetes-related kidney disease.

• The Nox5 isoform is expressed in humans but not in rats and mice, in vitro data indicate that Nox5 may play a significant role in the development of cardiovascular and renal disease.

• Evidence is indicating an isoform-specific role for Nox in the development of various diabetes-associated complications.

• Targeted pharmacological inhibition of Nox isoforms has been challenging due largely to lack of specificity in inhibitors, however, recently developed, more specific inhibitors including GKT137831 have proven to be effective in the treatment of diabetes-associated complications in animal models.

Notes