Effect of hereditary obesity on renal expressions of NO synthase, caveolin-1, AKt, guanylate cyclase, and calmodulin.

Obesity has emerged as a major cause of diabetes, cardiovascular disease, and renal insufficiency worldwide. Obese Zucker rats exhibit hyperphagia, obesity, insulin resistance, hyperlipidemia, and glomerulosclerosis and are frequently used as a model to study hereditary form of metabolic syndrome. Nitric oxide plays a major role in preservation of renal function and structure. The present study was designed to test the hypothesis that renal disease in this model may be associated with down-regulation of endothelial (eNOS) and neuromal NO synthases (nNOS) in the kidney. The study further sought to explore expressions of caveolin-1, phospho AKt, and calmodulin, which regulate activities of constituitive NOS isoforms, as well as soluble guanylate cyclase (sGC), which is involved in NO signaling. Twenty-two-week-old male obese and lean Zucker rats were studied. Body weight, serum lipids, urine albumin excretion, and renal tissue abundance of the above proteins were determined. Serum glucose and arterial pressure were unchanged, whereas urinary NO metabolite (NO(chi)) excretion and renal tissue nitrotyrosine abundance were markedly reduced (denoting depressed NO production) in the obese versus lean Zucker rats. This was accompanied by significant glomerulosclerosis, tubulointerstitial damage, renal immune cell infiltration, marked down-regulations of renal tissue eNOS and nNOS, mild reduction of caveolin-1, and unchanged calmodulin, phospho-AKt, and sGC. Hereditary obesity can result in down-regulations of kidney eNOS and nNOS, marked reduction of NO production, and glomerulosclerosis prior to the onset of frank diabetes and hypertension.