Fig. 2.

Obesity is characterized by elevated aldosterone and expanded extracellular volume. While oxidized fatty acids and adipokines stimulate aldosterone production from the adrenal gland, the hyperglycemia and insulin resistance of the metabolic syndrome impose a natriuretic handicap and subsequent volume expansion. This harmful interaction of inappropriately elevated aldosterone and expanded extracellular volume is the ‘double hit’ of obesity, leading to activation of non-epithelial mineralocorticoid receptors in the kidney. The resulting inflammation and fibrosis can lead to end-organ damage with glomerulosclerosis and proteinuria. This route of kidney injury occurs independent of obesity's well-known links to kidney disease via diabetes, hypertension, and dyslipidemia.