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      Vasoactive Factors and Tubulointerstitial Injury

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          Morphological changes of the tubulointerstitial architecture are a major determinant in the progression of chronic renal disease. The evolution of the tubulointerstitial lesion includes early tubular hypertrophy, recruitment of inflammatory cells into the tubulointerstitial space, and proliferation of interstitial fibroblasts resulting in the irreversible changes of tubular atrophy and tubulointerstitial fibrosis. Many of these diverse effects are mediated by autocrine or paracrine release of growth factors, cytokines, and chemokines. Proteinuria, reduction in functional renal mass per se, alterations in tubular fluid reabsorption, and well as hemodynamic changes in the injured kidney may all stimulate local release of such growth factors. A more recent conception is that vasoactive substances, traditionally viewed to be only involved in the regulation of vascular tone, could actually mediate many of these functions of the more 'classical’ growth factors and cytokines. In this regard, one of the most intensively studied vasoactive substances is angiotensin II which has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular hypertrophy and proliferation of interstitial fibroblasts. There is also increasing evidence that other vasoconstrictive factors such as endothelins and eicosanoids are involved in pathophysiological changes leading eventually to tubulointerstitial fibrosis. On the other hand, natriuretic peptides may exert antifibrogenic properties. Although interference with the renin angiotensin system is currently the only treatment being effective in attenuating the loss of function in patients with chronic renal insufficiency, it is likely that future studies will also investigate the role of other vasoactive substances in the progression of human chronic renal disease.

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          Natriuretic peptides.

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            Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group.

            Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide. We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 microgram per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality. The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, < 400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03). The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis.
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              Angiotensin II-mediated expression of p27Kip1 and induction of cellular hypertrophy in renal tubular cells depend on the generation of oxygen radicals.

              Angiotensin II (Ang II) induces hypertrophy of cultured proximal tubular cells. We have previously demonstrated that this Ang II-mediated hypertrophy occurs in the G1-phase of the cell cycle and depends on the induction of p27Kip1, an inhibitor of G1-phase cyclin/cyclin-dependent kinase complexes. The present study was undertaken to investigate whether Ang II may stimulate superoxide anions (O2.) formation in cultured LLC-PK1 and cultured mouse proximal tubule (MCT) cells, and to gain further insight into a potential relationship between O2. and cell cycle regulation. Reactive oxygen species were measured with the lucigenin method in intact cells. The effects of various inhibitors were tested on Ang II-induced O2. production. Cells were transiently transfected with phosphorothioate-modified rat p22phox antisense oligonucleotides to investigate the potential role of NAD(P)H oxidase. Expression of p22phox mRNA after Ang II-treatment was detected with Northern blots. Incorporation of [3H]leucine into de novo synthesized proteins was used as a parameter of cell hypertrophy. Expression of p27Kip1 was evaluated in cell lysates by Western blotting. Ang II stimulated the accumulation of O2. in tubular cells; however, an addition of two different antioxidants completely abolished measurable O2. This effect was transduced by angiotensin receptor type-1 (AT1) and was inhibited by a flavoprotein inhibitor (DIP) or p22phox antisense oligonucleotides, indicating the involvement of membrane NAD(P)H oxidase. Ang II-stimulated de novo protein synthesis was attenuated by DIP, antioxidants, and p22phox antisense oligonucleotides. The Ang II-induced expression of p27Kip1 protein and cellular hypertrophy were reduced by similar treatments. Generation of O2. by xanthine supplementation also stimulated p27Kip1 expression and induced hypertrophy in LLC-PK1 cells. This study provides the first evidence, to our knowledge, that Ang II induces O2. in cultured tubular cells. Ang II-mediated activation of membrane bound NAD(P)H oxidase, probably by an increase in p22phox transcripts, is likely responsible for this induction. Generation of O2. subsequently induces p27Kip1 expression and stimulates hypertrophy, suggesting a novel mechanism of how Ang II can modulate cell cycle regulation.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                18 May 1999
                : 22
                : 1-2
                : 62-70
                Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Germany
                25910 Kidney Blood Press Res 1999;22:62–70
                © 1999 S. Karger AG, Basel

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                Figures: 3, References: 89, Pages: 9
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