THE OVERALL OBJECTIVES ARE :
A) TO UNDERSTAND THE MECHANISM(S) OF NEPHROTOXIC LESIONS THAT AFFECT THE DIFFERENT REGIONS OF THE KIDNEY,
B) TO DEVELOP RELIABLE IN VITRO METHODS FOR TOXICITY SCREENING AND FOR THE DESIGN OF LESS NEPHROTOXIC DRUGS, AND
C) TO ESTABLISHED STRUCTURE ACTIVITY DATA ON CHEMICAL TOXICITY.
An investigation has been carried out on nephrotoxicity of drugs using in vitro methods, such as the intact but isolated perfused kidney, freshly isolated fragments representing the glomeruli and proximal tubules, primary cell cultures derived from these cells and cell lines derived from renal cells. The cells in these different systems were studied to assess how the presence of chemicals affected their function and structure. The study confirmed that several chemicals which damage discrete cell types in vivo, also adversely affect the same cell types in vitro. Similarly, if they do not damage a particular cell type in vivo, they are less likely to affect such cells in vitro. This means that the appropriate choice of renal cell types in vitro can indicate the potential nephrotoxicity of new chemcials. The use of appropriate cell types also enabled identification of early events in cellular injury that explain the basis of a chemical targeting for one cell type and not another. This may provide a rational way of limiting renal injury where life saving, but nephrotoxic, drugs have to be used. Progress was also made in using the simple kidney apparatus of the hagfish as a way of understanding the complex processes that occur in the mammalian kidney. Pig kidneys from abattoirs provided a large quantity of tissue for the isolation of cells as an alternative to laboratory animals.
THE SPECIFIC AIMS OF THIS PROPOSAL ARE TO IDENTIFY THE MECHANISMS OF TOXINS THAT TARGET VERY SELECTIVELY FOR THE PROXIMAL TUBULE, THE MEDULLA OR THE GLOMERULI, (THE THREE MOST FREQUENTLY AFFECTED SITES OF RENAL INJURY).
THE IN VITRO METHODS TO BE USED INCLUDE, PERFUSED KIDNEY, SLICES, TUBULAR FRAGMENTS AND GLOMERULI, PRIMARY MIXED AND HOMOGENEOUS CELL CULTURES AND ESTABLISHED RENAL LINES.KIDNEYS FROM COMMON LABORATORY ANIMALS AND SPECIAL STRAINS (IE MUNICH WISTAR RAT AND MYXINE GLUTINOSA, A FISH WITH A RELATIVELY SIMPLE KIDNEY), AND SPECIES WITH SPECIFIC CHARACTERISTICS (THE PIGKIDNEY IS VERY SIMILAR TO THAT OF MAN) WILL BE STUDIED.HUMAN TISSUE IS ALSO AVAILABLE FOR A FULL INTERSPECIES COMPARISON, WHICH IS NECESSARY IN ORDER TO VALIDATE THE CLINICAL USEFULNESS OF THE UNDERSTANDING OF THE MECHANISM(S) OF TOXICITY.CELL LINES WILL ALSO BE USED.
Funding SchemeCSC - Cost-sharing contracts