Back to 2011 Program

Introduction: The Objective of this study is to investigate the role of sphingosine kinase-2 in modulating renal injury induced by unilateral ureteral obstruction (UUO). Congenital Urinary tract obstruction is an important cause of renal injury and failure in children. While many aspects of the obstructive injury cascade are understood, this has not translated into therapeutic benefit. Sphingosine Kinase-2 (Sphk-2) is a metabolizing enzyme responsible for production of the bioactive lipid Sphingosine-1 Phosphate (S1P), which plays a major role in regulating the immune system, tissue injury and re-generation. Because of this, multiple Sphk inhibitors are under development and in the future Sphk inhibitors may see broad clinical use.
Materials & Methods:Genetically engineered Sphk-2 deficient and wild type mice were used in UUO model experiments. Contralateral kidneys served as control. Evaluation time points were 1,5 and 10 days. The renal pathology was examined by light microscopy. Expression levels of alpha-smooth muscle actin, TGF-b and Collagen type 1 were analyzed by RTPCR, immuno-histochemistry and western blotting.
Results:Wild type and Spkh-2 knock out mice showed significant differences. Mice expressing sphingosine kinase-2 showed extensive renal damage characterized by thickened cortical lesions, interstitial fibroblastic proliferation, focal interstitial hemorrhage, necrosis in lining of tubular epithelium and atrophic tubules. Sphk-2 knock out mice did not demonstrate this pattern of injury. Alpha smooth muscle actin and TGF-b expression levels were elevated in wild type obstructed kidneys when compared to knock out mice.
Conclusions:Our initial studies show that Sphk-2 -S1P pathway is implicated in the pathogenesis of obstructive renal injury.