Effects of Chronic Low-Level Cadmium Exposure on Glomerular Podocytes---Injury Mechanisms and Therapeutic Approaches

The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity of serum proteins in the kidney. Primary processes arise from the cell body and split into foot processes. 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. 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 cadmium exposure will not only lead to albuminuria but also predict the acceleration of chronic kidney disease progress. It is not known if low-level exposure to Cd induces an irreversible dysfunction in glomerular podocytes, which have a significant role in establishing the selective permeability of the kidney filtration barrier. In this 4-year proposal, we plan to use two cell models (low dose Cd treatment culture podocyte model, aortic endothelium primary culture) 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. We hypothesized 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. 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 additional possible risk marker 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:PC10207-0424
External Project ID:NSC102-2314-B182-019