Adiponectin regulates albuminuria and podocyte function in mice

J Clin Invest. 2008 May;118(5):1645-56. doi: 10.1172/JCI32691.

Abstract

Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad(-/-)) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad(-/-) mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens-1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad(-/-) mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases
  • Adiponectin / genetics
  • Adiponectin / metabolism*
  • Adult
  • Albumins / metabolism
  • Albuminuria / metabolism*
  • Animals
  • Cells, Cultured
  • Female
  • Humans
  • Kidney Diseases / etiology
  • Kidney Diseases / pathology
  • Kidney Diseases / urine
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multienzyme Complexes / metabolism
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Obesity / complications
  • Obesity / urine
  • Oxidative Stress
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Podocytes / cytology
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / physiology
  • Zonula Occludens-1 Protein

Substances

  • Adiponectin
  • Albumins
  • Membrane Proteins
  • Multienzyme Complexes
  • Phosphoproteins
  • TJP1 protein, human
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases