Sara Terryn

Cadmium is one of the heavy metals which are known as environmental contaminants with proven toxicity for humans and animals. In humans, cadmium exposure occurs via ingestion of polluted food and drinking-water or through inhalation of cadmium-dust (e.g. smoking), leading to an accumulation of cadmium in different tissues. Exposure to cadmium results in a variety of acute and chronic toxic effects depending on the dose, the route of entry and the form in which cadmium is taken up. The liver, kidney, lungs and small intestine are the main targets of cadmium accumulation. In the kidneys, it is well documented that cadmium induces among others nephropathy, characterized by abnormalities in renal tubule reabsorption. This abnormal tubular reabsorption primarily reflects defects in proximal tubule transport resembling those seen in Fanconi's syndrome (e.g. glucosuria, proteinuria, aminoaciduria, etc.).

The aims of this research project are first to establish a simple method for obtaining primary cultures of the mouse proximal tubule which are functionally and morphological intact (see figure 1 + 2) and secondly to characterize the properties of these primary cultures under control conditions and after acute or chronic exposure to cadmium.


Fig.1 + 2: Mouse proximal tubular cells in primary culture, grown on collagen-coated permeable filter supports. Cells display a typical epithelial morphology; cobblestone-like monolayer, apical microvilli, numerous mitochondria, apical-basolateral cell polarity (tight junctions at the apical pole and basolateral infolds),... .

Chronic Cd exposure eventually leads to end-stage renal failure, a process in which interstitial fibrosis plays an important role. Proximal tubular cells have been implicated in the development of interstitial fibrosis. When exposed to TGF-ß1, a profibrotic cytokine which is released in fibrotic lesions, proximal tubular cells can transdifferentiate into myofibroblasts. (Fig. 3 + 4) This process is called, epithelial to mesenchymal transdifferentiation (EMT). However the precise mechanisms that disrupt the integrity of the proximal tubule cell and lead to interstitial fibrosis and end-stage renal failure have to be eludicated.


Fig. 3 + 4: Primary cultures of mouse proximal tubular cells in normal (fig. 3) conditions and exposed to TGF-ß1 (fig. 4). TGF-ß1 induces EMT in proximal tubular cells; they transdifferentiate into myofibroblast (characterized by the presence of alpha-smooth muscle actin, brown color).