However, because TNF-α can also induce hypotension, it is impossible to distinguish direct cytokine effects on tubule cells from indirect effects of hypotension. Purified cytokines, such as TNF-α, can produce acute tubular necrosis when administered to experimental animals ( 21). High levels of these cytokines are produced during sepsis and have been demonstrated to mediate many of the pathophysiologic changes that occur among patients with sepsis ( 20).
A large body of data has demonstrated that the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interferon-γ (IFN-γ) are of central importance in septic shock ( 2, 20).
However, renal function can deteriorate without a reduction in renal blood flow ( 18, 19), demonstrating that nonhemodynamic factors are also important.
This is supported by studies demonstrating the presence of tubular casts in tissue sections and the recovery of viable and nonviable tubule cells from the urine of patients with ARF ( 5, 17). Tubule obstruction by shed cells and casts is a major factor leading to GFR reduction in ARF ( 16). Shed tubule cells aggregate into casts, which is possibly promoted by RGD-containing ligands, such as urinary fibronectin (Fn), that bridge integrins expressed on detached and in situ cells ( 13, 15). Dissolution of β 1 integrincell matrix adhesion results in tubule cell detachment from the basement membrane into the lumen ( 13) and may lead to tubule cell apoptosis ( 14). Hypoxia and ATP depletion disrupt actin microfilaments, producing loss of tubule cell polarity ( 9, 10, 11) in association with redistribution of basolateral α 3β 1 integrins to the apical cell compartment ( 12). Severe prolonged systemic hypotension in septic shock plays a major pathogenic role, leading to ischemic ARF characterized by marked alterations of the PTEC cytoskeleton ( 6, 7, 8). The key cells damaged in this process are proximal tubule epithelial cells (PTEC), and this damage produces pathologic changes termed acute tubular necrosis ( 4, 5). Severe sepsis and septic shock are major risk factors for the development of acute renal failure (ARF) ( 1), which has a complex pathogenesis ( 2, 3). Future therapeutic strategies aimed at specific iNOS inhibition might inhibit PTEC shedding after cytokine-induced injury and delay the onset of acute renal failure in sepsis. These studies provide a mechanism by which inflammatory cytokines induce PTEC damage in sepsis, in the absence of hypotension and ischemia. This interaction was downregulated by cytokines but was not dependent on NO. Attachment studies demonstrated that the major ligand involved in cell anchorage was laminin, probably through interactions with the integrin α 3β 1. These cells demonstrated coexpression of iNOS and apically redistributed β 1 integrins. Cell shedding was accompanied by dispersal of basolateral β 1 integrins and E-cadherin, with corresponding upregulation of integrin expression in clusters of cells elevated above the epithelial monolayer. Basolateral exposure of polarized PTEC monolayers to cytokines induced maximal NO-dependent cell shedding, mediated in part through NO effects on cGMP. Cytokines induced shedding of viable, apoptotic, and necrotic PTEC, which was dependent on NO synthesized by inducible NO synthase (iNOS) produced as a result of cytokine actions on PTEC. After exposure of human PTEC to tumor necrosis factor-α, interleukin-1α, and interferon-γ, the actin cytoskeleton was disrupted and cells became elongated, with extension of long filopodial processes. The question of whether the intermediate nitric oxide (NO) modulates these cytokine effects was also examined. This study examined the hypothesis that inflammatory cytokines, released early in sepsis, cause PTEC cytoskeletal damage and alter integrin-dependent cell-matrix adhesion. In sepsis-induced acute renal failure, actin cytoskeletal alterations result in shedding of proximal tubule epithelial cells (PTEC) and tubular obstruction.