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      Combination Therapy with Angiotensin-Converting Enzyme Inhibitor and Oral Adsorbent of Uremic Toxins Can Delay the Appearance of Glomerular Sclerosis and Interstitial Fibrosis in Established Renal Failure

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          Background/Aim: Angiotensin II plays a central role in the progression of chronic renal failure (CRF), and administration of angiotensin-converting enzyme inhibitor (ACEI) in rats delays the progression of CRF. However, ACEI has little effect on CRF progression in rats with established CRF. We therefore examined whether combination therapy with ACEI and oral adsorbent for uremic toxins in the gastrointestinal tract has the desired effect. Methods: Rats subjected to subtotal nephrectomy were given enalapril at 20 mg/kg (n = 10, group E), AST-120 at 5 g (n = 10, group A), enalapril and AST-120 together at the same doses (n = 10, group EA), or no treatment (n = 10, group C) 8 weeks after the operation. The substances were administered in 100 g rat chow. All animals were pair-fed, and all were killed after 8 weeks of pair-feeding. Results: Body weight did not differ between groups during the study. Blood pressure at week 8 was significantly lower in groups E and EA than in groups C and A (p < 0.05). Urinary protein excretion level and renal plasma flow rate at week 8 were significantly less in groups E and EA than in group C (p < 0.05, p < 0.01). The glomerular filtration rate at week 8 was significantly higher in group EA than in group C (p < 0.05). The glomerular sclerosis index and interstitial fibrosis area at week 8 were significantly less in group EA than in group C (p < 0.01). Conclusion: ACEI and AST-120 in combination can delay progression of established CRF in rats by inhibiting the appearance of glomerular sclerosis and interstitial fibrosis.

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          Most cited references 16

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          Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

          Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-beta plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease/protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-beta. Ang II treatment of rat mesangial cells in culture increased TGF-beta and matrix components biglycan, fibronectin, and collagen type I at both the mRNA and protein levels in a time- and dose-dependent manner. Saralasin, a competitive inhibitor of Ang II, prevented the stimulation. Ang II also promoted conversion of latent TGF-beta to the biologically active form. Coincubation of mesangial cells with Ang II and neutralizing antibody to TGF-beta blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-beta and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of TGF-beta expression. This mechanism may well contribute to glomerulosclerosis in vivo.
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            Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity.

            In uremic patients, various uremic toxins are accumulated and exert various biologic effects on uremia. Indoxyl sulfate (IS) is one of uremic toxins that is derived from dietary protein, and serum levels of IS are markedly increased in both uremic rats and patients. It has been previously reported that the accumulation of IS promotes the progression of chronic renal failure (CRF). This study demonstrates the role of rat organic anion transporters (rOATs) in the transport of IS and the induction of its nephrotoxicity. The administration of IS to 5/6-nephrectomized rats caused a faster progression of CRF, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules where rOAT1 (proximal tubules) and/or rOAT3 (proximal and distal tubules) were also shown to be localized. In in vitro study, the proximal tubular cells derived from mouse that stably express rOAT1 (S2 rOAT1) and rOAT3 (S2 rOAT3) were established. IS inhibited organic anion uptake by S2 rOAT1 and S2 rOAT3, and the Ki values were 34.2 and 74.4 microM, respectively. Compared with mock, S2 rOAT1 and S2 rOAT3 exhibited higher levels of IS uptake, which was inhibited by probenecid and cilastatin, organic anion transport inhibitors. The addition of IS induced a decrease in the viability of S2 rOAT1 and S2 rOAT3 as compared with the mock, which was rescued by probenecid. These results suggest that rOAT1 and rOAT3 play an important role in the transcellular transport of IS and the induction of its nephrotoxicity.
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              Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition.

              We studied the effects of interruption of the renin-angiotensin system (RAS) in rats that were volume depleted by water deprivation for 48 hours (AWD) with/without furosemide (AWD + F), a condition known to activate RAS. Following baseline micropuncture, AWD rats (N = 6) were treated with a specific angiotensin II type 1 receptor antagonist (AIIRA; 4 mg/kg body wt bolus i.v. and then continuous infusion) and glomerular hemodynamics compared to those obtained during angiotensin I converting enzyme inhibitor treatment (ACEI; 24 mg/kg bolus i.v. and then continuous infusion). Systemic blood pressure decreased equally following AIIRA and ACEI. Single nephron glomerular filtration rate (SNGFR) increased from baseline following AIIRA (24 nl/min vs. 30, P < 0.025). While a decrease in efferent arteriolar resistance (RE) reduced glomerular capillary pressure (PGC; 67 mm Hg vs. 60, P < 0.05), this change in RE together with decrease in afferent arteriolar resistance (RA), enhanced glomerular plasma flow rate (QA; 80 nl/min vs. 111). Antagonizing angiotensin II receptor increased QA which, together with the tendency to increase glomerular capillary ultrafiltration coefficient, Kf, served to improve glomerular filtration. By contrast, although inhibition of the angiotensin I converting enzyme caused greater vasodilatation, no increase in SNGFR occurred. The lack of response in filtration after ACEI was due to a further fall in PGC to 52 mm Hg (P < 0.01 vs. AIIRA), reflecting profound reduction in RE. Since ACEI but not AIIRA potentiates bradykinin activity we examined effects of a specific bradykinin antagonist (Hoe).(ABSTRACT TRUNCATED AT 250 WORDS)

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                September 2004
                08 September 2004
                : 27
                : 4
                : 218-225
                aSecond Department of Internal Medicine, Nihon University School of Medicine and bNihon University Graduate School of Business, Tokyo, Japan
                79869 Kidney Blood Press Res 2004;27:218–225
                © 2004 S. Karger AG, Basel

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                Figures: 4, Tables: 1, References: 29, Pages: 8
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