THERAPEUTIC EFFECT OF ARGININE-GLYCINE-ASPARTIC ACID PEPTIDES IN ACUTE RENAL INJURY

1. Previous studies from our laboratory have suggested that arginine-g lycine-aspartic acid (RGD) peptides, serving as a decoy, may prevent t ubular obstruction in the ischaemic model of acute renal failure. Spec ifically, we have demonstrated that: (i) stressed tubular epithelial c ells reverse the polarity of integrin receptors from the predominantly basolateral location to the apical cell membrane as a part of a more generalized process of the loss of epithelial cell polarity; (ii) depl etion of integrins expressed on the basal cell surface leads to the lo ss of anchorage to the basement membrane and cell desquamation; (iii) expression of integrin receptors on the apical cell membrane leads to indiscriminate interactions (e.g. the adhesion of desquamated cells to the cells remaining in situ), thus initiating the process of tubular obstruction; and (iv) conglomeration of the desquamated cells via inte grin receptors further aggravates tubular obstruction, 2. Importantly, these integrin-based interactions can be blocked by synthetic RGD pep tides. The linear RGD peptide injected into the renal artery upon rele ase of the renal artery damp prevented the elevation of proximal tubul ar hydrostatic pressure characteristically seen in animals with renal ischaemia that received injection of the vehicle of an inactive peptid e, 3. In vivo study of RGD peptides in ischaemic acute renal failure i n rats demonstrated attenuation of renal injury and accelerated recove ry of renal function, 4. Using linear RGD peptide labelled with Tc-99m , we have shown that this probe was retained in ischaemic kidneys, 5. To visualize RGD binding sites at the cellular level, we performed a m apping using fluorescent derivatives of two RGD peptides, a cyclic bio tinylated (Bt)-RGD peptide and a linear Rhodamine green-labelled (RhoG )-RGD peptide, 6. The findings suggest that the binding sites for RGD peptide are represented by the alpha V beta 3 integrin in the vasculat ure and some desquamated cells, whereas the majority of the desquamate d cells bind Bt-RGD via beta 1 integrins, 7. These findings were furth er tested using cultured endothelial cells co-incubated with leucocyte s. When co-incubation experiments were performed in the presence of cy clic RGD pentapeptide, the adhesion of HL-60 cells to both control and hypoxic endothelial monolayers was significantly reduced.