Endothelial or vascular smooth muscle cell-specific expression of human NOX5 exacerbates renal inflammation, fibrosis and albuminuria in the Akita mouse

Jha, J. C., Dai, A., Holterman, C. E., Cooper, M. E., Touyz, R. M. , Kennedy, C. R. and Jandeleit-Dahm, K. (2019) Endothelial or vascular smooth muscle cell-specific expression of human NOX5 exacerbates renal inflammation, fibrosis and albuminuria in the Akita mouse. Diabetologia, 62(9), pp. 1712-1726. (doi: 10.1007/s00125-019-4924-z) (PMID:31222503)

Abstract

Aims/hypothesis: Excessive production of reactive oxygen species (ROS) plays a detrimental role in the progression of diabetic kidney disease (DKD). Renal oxidative stress activates proinflammatory cytokines, chemokines and profibrotic factors in DKD. Increased expression of the prooxidant enzyme NADPH oxidase (NOX) 5 in kidneys of diabetic individuals has been hypothesised to correlate with renal injury and progression of DKD. Since the gene encoding NOX5 is not expressed in the mouse genome, we examined the effect of inducible human NOX5 expression in renal cells, selectively in either endothelial cells or vascular smooth muscle cells (VSMCs)/mesangial cells in a model of insulin-deficient diabetes, the Akita mouse. Methods: Renal structural injury, including glomerulosclerosis, mesangial expansion and extracellular matrix protein accumulation, as well as renal inflammation, ROS formation and albuminuria, were examined in the NOX5 transgenic Akita mouse model of DKD. Results: Expression of NOX5 in either endothelial cells or VSMCs/mesangial cells in diabetic Akita mice was associated with increased renal inflammation (monocyte chemoattractant protein-1, NF-κB and toll-like receptor-4) and glomerulosclerosis, as well as upregulation of protein kinase C-α and increased expression of extracellular matrix genes (encoding collagen III, fibronectin and α-smooth muscle actin) and proteins (collagen IV), most likely mediated via enhanced renal ROS production. The effect of VSMC/mesangial cell-specific NOX5 expression resulted in more pronounced renal fibrosis in comparison with endothelial cell-specific NOX5 expression in diabetic mice. In addition, albuminuria was significantly increased in diabetic VEcad+NOX5+ mice (1192 ± 194 μg/24 h) when compared with diabetic VEcad+NOX5− mice (770 ± 98 μg/24 h). Furthermore, the regulatory components of NOX5 activation, including heat shock protein 90 and transient receptor potential cation channel subfamily C member 6, were upregulated only in the presence of both NOX5 and diabetes. Conclusions/interpretation: The findings from this study highlight the importance of NOX5 in promoting diabetes-related renal injury and provide the rationale for the development of a selective NOX5 inhibitor for the prevention and/or treatment of DKD.

• Item Type: Articles
• Additional Information: This work was supported by the National Health & Medical Research Council of Australia, a JDRF Program/Project Grant. KJD and MEC are supported by NHMRC Senior Principal Research Fellowships, respectively. JCJ is supported by JDRF and an NHMRC- Early Career Fellowship.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Touyz, Professor Rhian
• Authors: Jha, J. C., Dai, A., Holterman, C. E., Cooper, M. E., Touyz, R. M., Kennedy, C. R., and Jandeleit-Dahm, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Diabetologia
• Publisher: Springer
• ISSN: 0012-186X
• ISSN (Online): 1432-0428
• Published Online: 20 June 2019
• Copyright Holders: Copyright © 2019 Springer-Verlag GmbH Germany, part of Springer Nature
• First Published: First published in Diabetologia 62(9):1712-1726
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher