Enhancement of Renal Tubular Epithelial Cell Barrier Function by the Immunosuppressant Drugs Cyclosporine A and Sirolimus

ABSTRACT

The primary function of the kidney includes the elimination of waste products and the maintenance of fluid and electrolyte composition of the body. The functioning unit of the kidney is the nephron including the glomerulus with a filtration function and the tubule with a reabsorption and secretion function. The fluid and electrolyte homeostasis is achieved largely through selective, vectorial transport facilitated by the renal tubular epithelium. This involves both transcellular and paracellular transport. Paracellular transport across renal tubular epithelial tight junctions (TJs) varies in different parts of the nephron. The relative concentrations of different claudins that are located in the TJ at any time determine the ion and size selectivity of the paracellular diffusion pathway in the kidney as in other tissues. In this article, we review work from our own laboratory and others providing evidence that immunosuppressive drugs, especially cyclosporine A (CsA) and sirolimus (SRL) and can alter transport molecules in kidney tubules. We outline evidence that CsA and SRL can enhance renal epithelial barrier function as indicated by transepithelial electrical resistance (TEER). The possible signalling mechanisms involved in altering the TJs and claudins by CsA and SRL are outlined and involve both TGF-β1 and the ERK 1/2. These effects of CsA and SRL on kidney epithelia cell barrier function may help to explain some of the renal transport defects and nephrotoxicity seen with CsA and SRL. However if similar effects occur systemically in vivo, with these two immunosuppressive drugs, the enhancement of barrier function in areas of the body may decrease luminal antigen presentation, decreasing immune activation and support the immunosuppressive action of these drugs.