(593v) Adiponectin Levels Modulate Recovery of Renal Function in a Novel Model of Podocyte Ablation

Objective: Adiponectin is altered in numerous diseases with renal pathologies: low levels are associated with the metabolic syndrome and Type II diabetes while heightened levels are often concurrent with chronic kidney disease and Type I diabetes. To explore the effects of adiponectin on kidney disease progression, we have created a novel murine model of podocyte apoptosis using a unique PODocin promoter driven cassette for Apoptosis Through Targeted Activation of Caspase 8 (“POD-ATTAC”).

Methods and Results: The podocyte-expressed ATTAC fusion protein contains a mutant FKBP domain that binds specifically to the low-molecular weight AP20187 “dimerizer”. Dimerization of the ATTAC fusion protein induces caspase-8 activation resulting in rapid podocyte-specific apoptosis. Podocyte loss is the first step in many clinically-important nephropathies. The number of podocytes ablated, overall renal functional insult, and kidney disease progression are highly dimerizer dose-dependent providing a titratable model: dosing permits POD-ATTAC mice to mimic many levels of human nephropathies and potentially restore podocyte number and function. POD-ATTAC mice lacking adiponectin develop irreversible albuminuria and renal failure over time. Adiponectin over-expressing POD-ATTAC mice, conversely, demonstrate rapid recovery and exhibit limited interstitial fibrosis despite similar numbers of podocytes ablated. Unlike overexpression, moderately raising serum adiponectin levels with an agonist for the nuclear receptor PPARγ fails to confer sufficient renal protection or recovery potential.

Conclusions: The novel POD-ATTAC mouse model provides an excellent platform for further studies of precisely timed podocyte injury, kidney disease progression, and functional regeneration. Our data also highlights the powerful protective role of the adipokine adiponectin in cardio-renal physiology.

Acknowledgement: JMR was supported in part by NIH F32-DK085935