Peri‐renal Adipose Tissue Inflammation Possibly Underlies Mild Renal Dysfunction in Early Metabolic Challenge

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Cardiovascular disease remains a primary cause of morbidity and mortality in patients with diabetes. Cardiovascular complications in those patients are independent of glycemic control; intensive antihyperglycemic therapy was found to be ineffective in improving the prognosis of these complications. Evidence of vascular function deterioration in prediabetic patients implicates the involvement of mechanisms other than hyperglycemia in the development of cardiovascular dysfunction. Adipose inflammation constitutes a possible mechanism that is involved in the pathogenesis of diabetes and metabolic syndrome. We developed a rat model of mild hypercaloric (HC) stress with a delayed development of hyperglycemia to investigate the mechanism of cadiovascular dysfunction in early stages of metabolic challenge. We previously reported that prior to the development of hyperglycemia, perivascular adipose tissue inflammation was associated with cardiovascular structural and functional anomalies. No changes in blood glucose, body weight or blood pressure levels were observed in this rat model. Systemic inflammation was not detected in this rat model, however following 12 weeks of HC feeding, peri‐renal adipose tissue showed increased oxidative stress and inflammatory cytokine expression (IL‐1b). Moreover, proteinuria and hyperfiltration indicated an early stage of renovascular dysfunction. This renovascular dysfunction manifested as (1) loss of proper endothelial feedback, (2) loss of prostaglandin and nitric oxide activity, and (3) an uncontrolled vasodilation induced by upregulation of epoxyeicosatrienoic acid effect. Moreover, the renovascular dysfunction was associated with significant increases in renal oxidative stress, inflammatory mediators (IL‐1b and TGF‐b1) and culminated in renal structural damage. Glomerulosclerosis was increased following HC feeding as well as significant increases in the expression of a‐smooth muscle actin in proximal tubular cells suggesting possible epithelial to mesenchymal transformation. Ameliorating adipose inflammation by a two‐week treatment with non‐hypoglycemic doses of metformin (100 mg/Kg/day) or pioglitazone (2.5 mg/Kg/day), improved renovascular function and structural nephrotoxicity. These results provide evidence of an early progressive renal damage induced by localized perirenal adipose tissue inflammation in prediabetes.Support or Funding InformationResearch support: AUB‐FM grant #320186