In the current issue of the JCI
, Sharma et al. describe a role of adiponectin in the pathogenesis of albuminuria (7
). Adiponectin is secreted exclusively by adipocytes (8
). The monomer is a 30-kDa protein with 3 distinct domains: N-terminal hypervariable region, collagenous stalk, and C-terminal globular domain (8
). Adiponectin circulates in plasma as various complexes: high–molecular weight (HMW; 12- to 36-mer), low–molecular weight (hexamer), and trimeric forms. Total and HMW adiponectin levels are more abundant in females and decline in obesity (8
). Low adiponectin levels are related to higher prevalence of type 2 diabetes, inflammation, and atherosclerosis, and these abnormalities are reversed by adiponectin treatment (8
). The insulin-sensitizing effect of thiazolidinediones is related to increased HMW adiponectin levels (9
Previously, adiponectin receptors AdipoR1 and AdipoR2 — containing 7-transmembrane domains that are structurally and functionally distinct from G protein–coupled receptors — have been described (8
). AdipoR1 is more widely expressed and enriched in muscle, while AdipoR2 is abundant in liver. Binding of adiponectin to AdipoR1 and AdipoR2 increases AMPK activation and PPARα signaling, resulting in suppression of gluconeogenesis, stimulation of fatty acid oxidation, and amelioration of diabetes (8
). AdipoR1- and AdipoR2-mediated signal transduction has been implicated in steatosis, inflammation, and oxidative stress, all key abnormalities associated with obesity and the metabolic syndrome (8
Sharma et al. found that plasma adiponectin concentration was inversely related to urinary albumin excretion in obese African Americans, a group prone to obesity and chronic kidney disease (7
). Conversely, BMI, blood pressure, lipid levels, and plasma levels of IL-6 and plasminogen activator inhibitor–1 (PAI-1) were not associated with albuminuria in this group. To establish a role of adiponectin in the pathogenesis of albuminuria, Sharma et al. compared wild-type mice with adiponectin-deficient mice. Blood pressure, glucose levels, and lipid levels were not affected in Ad–/–
mice fed a regular rodent diet; however, albuminuria was significantly higher, worsened with age, and was exacerbated by diabetes. Hydrogen peroxide levels increased in the urine of Ad–/–
mice, consistent with oxidative stress. Electron microscopic examination revealed segmental fusion of the feet processes of podocytes (interdigitated cells that closely invest the glomerular capillary network in the kidney, as shown in Figures and , and act in part as a filter for large macromolecules) in Ad–/–
mice, although the thickness of the glomerular basement membrane and the structures of endothelial and mesangial cells were not altered by adiponectin deficiency. Albumin permeability was increased in a monolayer culture of podocytes from Ad–/–
mice, consistent with albuminuria in this model.
Schematic demonstrating the interdigitation of podocyte foot processes that surround glomerular capillaries.
Schematic illustration of the effects of adiponectin on podocytes.
The authors showed that AdipoR1 was highly expressed in podocytes (7
). AMPK phosphorylation was increased in podocytes by adiponectin or the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR; Figure A). The distribution of the tight junction protein zonula occludens–1 (ZO-1) was disrupted in podocytes from Ad–/–
mice and restored by adiponectin or AICAR treatment. Although the involvement of AdipoR1 in albuminuria and how this is coupled to AMPK signaling requires further study, these results demonstrate major effects of adiponectin on the kidney.