Anti-Oxidant and Anti-Inflammatory Agent Celastrol Can Attenuate Chronic Low-Level Cadmium Exposure Induced Glomerular Podocyte Injuries

Cadmium (Cd) is an important industrial and environmental heavy metal pollutant that with chronic, low-level patterns of exposure the kidney is the primary target of toxicity. Recent reports demonstrated that long-term low level of Cd exposure will not only lead to albuminuria but also predict the acceleration of chronic kidney disease (CKD) progress. It is not known if low-level exposure to Cd induces an irreversible dysfunction in glomerular podocytes. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity of serum proteins in the kidney. Podocyte foot processes comprise a highly branched interdigitating network with foot processes of neighboring podocytes connected by the slit membrane, which is a multi-protein complex similar to adheren junctions and covers filtration slits, thereby establishing the final barrier to urinary protein loss. Proteinuria, especially albuminuria, mainly caused by podocyte injury and ensuing filtration barrier failure, predicts progression and renal outcomes in human glomerular diseases. Our current results demonstrated that long-term low concentration of Cd exposure, will induce intracellular oxidative stress, and result in endoplasmic reticulum stress then impairing podocyte protein synthesis. These toxic effects compromise cell survival pathways, such as Akt and Erk, then finally led to podocyte apoptosis. Alteration in podocyte number (or podocyte depletion) can generate filtration barrier failure, proteinuria and focal segmental glomerulosclerosis, which is a very common primary glomerular disease that terminates as end-stage renal disease. In this 3-year proposal, we plan to use three cell models (low dose Cd treatment culture podocyte model, aortic endothelium primary culture, podocyte cultured on nano-porous membranes micro-fluid device) and three animal models (Cd-infusion rat, Cd-infusion rat with wound creation, 5/6 nephretomy rat with Cd-infusion) to study the injurious effects of chronic, low level Cd exposure to glomerular podocytes and vascular endothelium. Celastrol, an anti-oxidant and anti-inflammatory agent, will be explored for its novel therapeutic use in Cd-induced kidney injuries. Cadmium exposure may also cause damage to the vascular endothelial cells, as presented with delayed skin wound healing due to poor neovascularization. The development of albuminuria has been identified as an independent risk factor that is almost unique to patients with CKD and a marker for predicting cardiovascular disease risk. By statistically correlating functional parameters obtained from the thee animal experiments (increased albuminuria and decreased glomerular filtration rate) and molecular biologic parameters (increased glomerular podocyte apoptosis, reduced wound healing rate, reducing angiogenesis in sin), we will verify if that long-term low level of cadmium exposure can represent as a suitable experimentally translational medicine model as high oxidative stress on the cardiovascular system.

Project ID:PC10307-0138
External Project ID:MOST103-2314-B182A-114