This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 53/6/925    most recent HYPERTENSIONAHA.108.122812v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Sharkey, D. Articles by Budge, H. PubMed PubMed Citation Articles by Sharkey, D. Articles by Budge, H. Related Collections Obesity Animal models of human disease

(Hypertension. 2009;53:925.)
© 2009 American Heart Association, Inc.

Original Articles

Impact of Early Onset Obesity and Hypertension on the Unfolded Protein Response in Renal Tissues of Juvenile Sheep

Don Sharkey; Hernan P. Fainberg; Vicky Wilson; Emma Harvey; David S. Gardner; Michael E. Symonds; Helen Budge

From the Centre for Reproduction and Early Life, Institute of Clinical Research (D.S., H.P.F., V.W., E.H., M.E.S., H.B.), and School of Veterinary Sciences (D.S.G.), University of Nottingham, Nottingham, United Kingdom.

Correspondence to Michael E. Symonds, Academic Child Health, School of Clinical Sciences, E Floor East Block, University Hospital, Nottingham, NG7 2UH United Kingdom. E-mail michael.symonds{at}nottingham.ac.uk

Childhood obesity has reached epidemic proportions. Obesity is an independent risk factor for the development of end-stage renal disease. Endoplasmic reticulum stress and subsequent activation of the unfolded protein response (UPR) are implicated in the development of adipose tissue dysregulation and type 2 diabetes mellitus in obesity. The present study explored the impact of adolescent-onset obesity on the UPR after obesity-related hypertension and nephropathy, using an ovine model in which obesity was induced by increased food intake and reduced activity. Obese young adults had a higher mean arterial pressure (lean, 89.6±1.7 mm Hg versus obese, 101±3.0 mm Hg; P<0.01) and greater sensitivity to low physiological doses of angiotensin II. Obesity increased the glomerular area and was associated with activation of the UPR in renal cells with a greater abundance of glucose-regulated protein 78, C/EBP homologous protein, Bax, phosphorylated c-Jun amino-terminal kinase, and activating transcription factor 6 (all P<0.05). In addition, there was a marked upregulation of proinflammatory genes, most notably those involved in macrophage signaling. Reactive oxygen species production and handling were also perturbed in obese adults. Renal endoplasmic reticulum stress was positively correlated with macrophage content (r=0.83; P<0.001), phosphorylated c-Jun amino-terminal kinase (r=0.73; P<0.01), and adiposity (r=0.71; P<0.01). In conclusion, adolescent-onset, obesity-related renal endoplasmic reticulum stress was associated with activation of the UPR, apoptosis, and inflammation, potentially increasing the associated renal damage observed in young adults. The UPR may prove to be a useful therapeutic target for the treatment and prevention of obesity-related nephropathy and associated hypertension, thereby reducing the burden of end-stage renal disease.

Key Words: obesity • hypertension • unfolded protein response • nephropathy • adolescence • kidney

This article has been cited by other articles:

				C. Marchesi, T. Ebrahimian, O. Angulo, P. Paradis, and E. L. Schiffrin Endothelial Nitric Oxide Synthase Uncoupling and Perivascular Adipose Oxidative Stress and Inflammation Contribute to Vascular Dysfunction in a Rodent Model of Metabolic Syndrome Hypertension, December 1, 2009; 54(6): 1384 - 1392. [Abstract] [Full Text] [PDF]