Pathogenetic role of Arg-Gly-Asp-recognizing integrins in acute renal failure. off.

Abstract

Reorientation of the a3 subunit of integrins from predominantly basal to the apical cell surface of cultured renal tubular epithelial cells subjected to oxidant stress has previously been demonstrated. The present study was designed to assess functional competence of ectopically expressed apical integrins. Cell-cell adhesion assay revealed enhanced cytoattractant properties of stressed cells. Stressed epithelial cells exhibited specific recognition and binding of laminin-coated latex beads. These processes were inhibited with the peptide Gly-Arg-Gly-Asp-Asn-Pro (GRGDNP) suggesting a role of RGD-recognizing integrins in augmented adhesion to stressed cells. Given that such enhanced adhesion in in vivo acute renal failure may govern tubular obstruction by desquamated epithelium, a physiological marker of patency of tubular lumen, proximal tubular pressure, was monitored in rats subjected to 60 min of renal ischemia followed by reperfusion. Proximal tubular pressure increased 2-fold after 2 hr of reperfusion in animals that had undergone 60 min of ischemia. Infusion of GRGDNP into the renal artery during reperfusion period virtually abolished an increase in proximal tubular pressure observed in ischemic acute renal failure. These in vitro and in vivo findings are consistent with the hypothesis that RGDrecognizing integrins play an important role in the pathogenesis of tubular obstruction in ischemic acute renal failure.Acute renal failure is a frequent complication of diverse ischemic, nephrotoxic, and nephritic insults to the kidney all of which invariably produce obstruction of renal tubules by desquamated cells and debris. The pathogenetic role of tubular obstruction in the development of acute renal failure has been established in a series of microdissection studies (1,2) and further advanced by servo-null pressure monitoring, which revealed an elevation of proximal tubular pressure after diverse renal insults (3-6). It has been found that after renal insults, the majority ofdesquamated cells are viable and contribute to the development of tubular obstruction (7).These findings provided a rationale for our investigations into the stress-induced derangement of cell-matrix adhesion and facilitated cell-cell adhesion of renal tubular epithelial cells. Indeed, oxidant stress to renal epithelia resulted in redistribution of several subunits of integrin receptors from the predominantly basal location to the apical cell membrane (8). This phenomenon has underscored both the detachment of cells from the matrix and their potential cytoattractant properties (8,9). The present study was undertaken to examine cytoattractive properties of stressed epithelial cells in vitro and in vivo, as well as the involvement of integrin receptors in this process. Given that many integrin receptors recognize the Arg-Gly-Asp (RGD) sequence presented by matrix proteins (10-13), the effect of synthetic RGD peptidesThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereb...

Acute renal failure: definitions, diagnosis, pathogenesis, and therapy

“…binding to Arg-Gly-Asp (RGD) sequences (47). In support of this possibility, synthetic cyclical RGD compounds administered during the reperfusion period have been shown to attenuate tubular obstruction and to reverse the related increase in proximal tubular pressure (48). Relief of tubular obstruction in experimental ARF, as assessed by nephron micropuncture, has also been shown with a solute diuresis induced by mannitol (49).…”

Arg-Gly-Asp (RGD) Peptides and Peptidomimetics as Therapeutics: Relevance for Renal Diseases

“…A detailed discussion is outwith the scope of this review, but indicates the range of clinical conditions whose progress could be modified by the therapeutic use of integrin antagonists. The best characterised is the use of ‘RGD peptides’ in modifying the progress of experimental acute tubular necrosis [30, 31, 32]. Here renal tubules are blocked by sloughed and aggregated, damaged tubular epithelial cells, and the process is ameliorated by RGD peptides interfering with cell-cell interactions mediated by α 3 β 1 and other integrins.…”

Role of fibrinogen in acute ischemic kidney injury

“…However, it is possible that the presence of fibrinogen that we observed in renal tubules might have contributed to the better outcome in heterozygous mice. Through its integrinbinding domains, fibrinogen might diminish the adhesion of desquamated epithelial cells that would otherwise form casts (16). In this case, the antiadhesive properties of fibrinogen would have a beneficial effect by helping to avoid tubular obstruction.…”