(623ai) Adiponectin Levels Mediate Recovery of Renal Function In a Novel Model of Podocyte Ablation

Adiponectin levels are altered in renal pathologies: low levels are associated with metabolic dysfunction and type II diabetes while heightened levels have been measured in chronic kidney disease. To explore the effects of adiponectin on kidney disease progression, a novel murine model of podocyte apoptosis was created using a PODocin promoter driven cassette for Apoptosis Through Targeted Activation of Caspase 8 (POD-ATTAC). Upon induction by a low molecular weight dimerizing agent, the ATTAC construct induces caspase-mediated apoptosis in a cell-specific manner. These mice not only demonstrated significant kidney damage to mimic human renal disease, but also restored podocyte filtration function over time in a dimerizer dose-dependent manner. Adiponectin knockout POD-ATTAC mice developed massive, irreversible albuminuria and renal failure over time, while adiponectin over-expressing (OE) POD-ATTAC mice demonstrated rapid recovery from heightened albuminuria. Renal histology in OE kidneys following recovery showed improved overall renal health with reduced interstitial fibrosis suggesting protective effects of adiponectin throughout the kidney. Thus, despite similar number of podocytes ablated as compared to wildtype POD-ATTAC mice, these findings demonstrate that increased adiponectin levels in OE mice prevent damage to other renal cell types and progression to renal failure. The POD-ATTAC model provides an excellent platform for further studies of podocyte regeneration and potential roles of adiponectin on renal function in chronic kidney disease.