Albuminuria is a strong and independent predictor of
kidney disease progression but the mechanisms of
albumin handling by the kidney remain to be fully defined. Previous studies have shown that podocytes endocytose
albumin. Here we demonstrate that Shank2, a large scaffolding
protein originally identified at the neuronal postsynaptic density, is expressed in podocytes in vivo and in vitro and plays an important role in
albumin endocytosis in podocytes. Knockdown of Shank2 in cultured human podocytes decreased
albumin uptake, but the decrease was not statistically significant likely due to residual Shank2 still present in the knockdown podocytes. Complete knockout of Shank2 in podocytes significantly diminished
albumin uptake in vitro. Shank2 knockout mice develop
proteinuria by 8 weeks of age. To examine
albumin handling in vivo in wild-type and Shank2 knockout mice we used multiphoton intravital imaging. While
FITC-labeled
albumin was rapidly seen in the renal tubules of wild-type mice after injection, little
albumin was seen in the tubules of Shank2 knockout mice indicating dysregulated renal
albumin trafficking in the Shank2 knockouts. We have previously found that
caveolin-1 is required for
albumin endocytosis in cultured podocytes. Shank2 knockout mice had significantly decreased expression and altered localization of
caveolin-1 in podocytes suggesting that disruption of
albumin endocytosis in Shank2 knockouts is mediated via
caveolin-1. In summary, we have identified Shank2 as another component of the
albumin endocytic pathway in podocytes.