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Renal tubulointerstitial fibrosis - New thoughts on its development and progression

POSTGRADUATE MEDICINE 2000年第1期108卷 159-+页

作者： O'Donnell, MP Minneapolis Med Res Fdn Inc Minneapolis MN 55404 USA Hennepin Cty Med Ctr Dept Med Div Nephrol Minneapolis MN 55415 USA

Tubulointerstitial fibrosis, characterized by accumulation of extracellular matrix proteins, is a morphologic hallmark of chronic renal disease as well as a component of normal aging in the kidney and of chronic allograft nephropathy. In this article, the author describes patterns that have recently been proposed to explain the pathogenesis of tubulointerstitial injury. In addition, he discusses available and experimental pharmacologic interventions that may ameliorate renal fibrosis.

关键词：血管紧张素ⅱ/代谢上皮/生理学纤维化肾功能衰竭慢性/药物疗法肾功能衰竭慢性/病理学肾功能衰竭慢性/病理生理学肾小管/代谢肾小管/病理学肾小管/病理生理学转化生长因子β/生理学人类

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Transport of [³H]losartan across isolated perfused rabbit proximal tubule

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期290卷 38-42页

作者： Edwards, RM Stack, EJ Trizna, W SmithKline Beecham Pharmaceut Dept Renal Pharmacol King Of Prussia PA 19406 USA

The transport of the angiotensin II receptor antagonist rosarian and its interaction with organic anion transport were examined in the isolated perfused rabbit proximal tubule. Losartan reversibly inhibited the secretion of para-aminohippurate (PAH) in a concentration-dependent manner (IC50 = 15 +/- 0.5 mu M). Other angiotensin II receptor antagonists also inhibited PAH secretion with similar potencies: eprosartan, 11 +/- 2.3 mu M;irbesartan, 17 +/- 2.2 mu M, and valsartan 3 +/- 0.6 mu M. [H-3]Losartan was secreted by the proximal tubule by a saturable and probenecid-sensitive mechanism. The affinity of losartan for the organic anion transporter (K-m = 12.3 +/- 1.8 mu M) was significantly greater than that of PAH (K-m = 88.5 +/- 10.7 mu M) [H-3]losartan secretion was stimulated in the presence of cu-ketoglutarate, suggesting that losartan, like PAH, enters the cell in exchange for a dicarboxylate. These results demonstrate that losartan and probably other nonpeptide angiotensin II receptor antagonists are secreted by an organic anion transporter that is similar to, if not identical with, the classic PAH transporter.

关键词：血管紧张素ⅱ/代谢酮戊二酸类/药理学肾小管近端/代谢洛沙坦/代谢灌流丙磺舒/药理学受体血管紧张素/拮抗剂和抑制剂肾脏用药/药理学 p-氨基马尿酸/代谢 p-氨基马尿酸/药理学动物男(雄)性兔

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Pathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy - Implications for the pathogenesis of tubulointerstitial fibrosis

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AMERICAN JOURNAL OF PATHOLOGY 1999年第2期155卷 429-440页

作者： Gilbert, RE Wu, LL Kelly, DJ Cox, A Wilkinson-Berka, JL Johnston, CI Cooper, ME Univ Melbourne Dept Med Heidelberg Vic 3081 Australia Univ Melbourne Austin & Repatriat Med Ctr Heidelberg Vic 3081 Australia Univ Melbourne Dept Physiol Heidelberg Vic 3081 Australia

The finding that the systemic renin-angiotensin system (RAS) is not activated in most types of chronic renal disease has led to the suggestion that a local, intrarenal RAS may be an important determinant in the relentless progression of renal disease. Therefore, cell specific changes in various components of the RAS in response to renal mass reduction and angiotensin converting enzyme (ACE) inhibition were examined. Thirty Sprague-Dawley rats mere randomly assigned to sham surgery, subtotal nephrectomy (STNx) alone or STNx treated with the ACE inhibitor, perindopril, and sacrificed after 12 weeks, In sham rats, renin mRNA and protein were only present in the juxtaglomerular apparatus, In contrast, in STNx kidneys, renin and angiotensin II expression mere noted predominantly in renal tubular epithelial cells in association with overexpression of the prosclerotic cytokine, transforming growth factor-beta 1 (TGF-beta 1), In perindopril-treated STNx rats expression of renin and TGF-beta 1 were similar to control animals. These finding indicate that following renal mass reduction there is pathological tubular expression of various components of the RAS, Furthermore, in contrast to the juxtaglomerular apparatus, tubular renin expression was reduced with. ACE inhibition. These changes within the intrarenal RAS may be pathogenetically Linked to the development of tubulointerstitial injury.

关键词：血管紧张素Ⅱ/分析血管紧张素ⅱ/代谢胶原/分析胶原/代谢免疫组织化学原位杂交肾/解剖学和组织学肾/病理学肾/外科学肾小管/解剖学和组织学肾小管/代谢肾小管/外科学肾切除术肾炎间质性/代谢肽基二肽酶A/分析肽基二肽酶A/代谢大鼠 Sprague-Dawley 肾素/分析肾素/代谢转化生长因子α/分析转化生长因子α/代谢转化生长因子β/分析转化生长因子β/代谢动物男(雄)性大鼠

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Structural comparison between type I and type II antagonists: Possible implications in the drug design of AT1 antagonists

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第8期10卷 755-758页

作者： Roumelioti, P Tselios, T Alexopoulos, K Mavromoustakos, T Kolocouris, A Moore, GJ Matsoukas, JM Natl Hellen Res Fdn Inst Organ & Pharmaceut Chem Athens 11635 Greece Univ Patras Dept Chem Patras 26500 Greece Univ Calgary Dept Pharmacol & Therapeut Calgary AB T2N 4N1 Canada

Analogues of sarilesin (type I AT1 antagonists), and sarmesin (type II AT1 antagonists) with homoserine (hSer) at position 8 were prepared and bioassayed. The presence of a Tyr(4)-Ile(5)-His(6) bend found in sarmesin but not in sarilesin was identified. The obtained results coupled with conformational analysis studies, using a combination of NMR spectroscopy and computational chemistry, propose important conformational and stereoelectronic properties for agonist and antagonist activity at ATI receptors. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：血管紧张素Ⅰ/代谢血管紧张素Ⅱ/类似物和衍生物血管紧张素Ⅱ/化学合成血管紧张素Ⅱ/化学血管紧张素ⅱ/代谢血管紧张素Ⅱ/药理学血管紧张素受体拮抗剂药物设计磁共振波谱学模型分子受体血管紧张素/代谢构效关系子宫/药物作用动物女(雌)性大鼠

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Up-regulation of AT1 and AT₂ receptors in postinfarcted hypertrophied myocytes and stretch-mediated apoptotic cell death

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AMERICAN JOURNAL OF PATHOLOGY 2000年第5期156卷 1663-1672页

作者： Leri, A Liu, Y Li, BS Fiordaliso, F Malhotra, A Latini, R Kajstura, J Anversa, P New York Med Coll Dept Med Valhalla NY 10595 USA Ist Ric Farmacol Mario Negri Milan Italy

To determine whether up-regulation of AT(1) and AT(2) receptors occurred in hypertrophied myocytes after infarction and whether AT(2) played a role in stretch-mediated apoptosis, left ventricular myocytes were dissociated from the surviving portion of the wall 8 days after coronary occlusion and cardiac failure in rats. Control cells were obtained from sham-operated animals. Myocytes were stretched in an equibiaxial stretch apparatus and angiotensin II (Ang II) formation and cell death were measured 3 and. 12 hours later. AT(1) and AT(2) proteins were evaluated in freshly isolated myocytes and after stretch. The effects of AT(1) and AT(2) antagonists on stretch-induced Ang II synthesis and apoptosis were also established. Myocardial infarction increased AT(1) and AT(2) in myocytes and stretch further up-regulated these receptors. Ang II levels were higher in postinfarcted myocytes and this peptide increased with the duration of stretch in both groups of cells. Similarly, apoptosis increased with time in control and postinfarcted myocytes. Absolute values of Ang II and apoptosis were greater in myocytes from infarcted hearts at 3 and 12 hours after stretch. Addition of AT(1) blocker to cultures Inhibited stretch-activated apoptosis in both myocyte populations as well as the generation of Ang II in postinfarcted myocytes. In contrast, AT(2) antagonists had no impact on these cellular events. In conclusion, Ang II stimulated cell death through AT(1) receptor activation, whereas Ligand binding to AT(2) receptor did not alter Ang II concentration and apoptosis in normal and postinfarcted hypertrophied myocytes.

关键词：血管紧张素ⅱ/代谢细胞凋亡体重细胞死亡细胞大小细胞培养的心室/细胞学心室/代谢心室/病理生理学肥大左心室/代谢肥大左心室/病理学心肌梗死/代谢心肌梗死/病理学大鼠 Sprague-Dawley 受体血管紧张素/代谢应力物理时间因素增量调节动物男(雄)性大鼠

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Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: Effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 295-303页

作者： Duncan, AM James, GM Anastasopoulos, F Kladis, A Briscoe, TA Campbell, DJ St Vincents Inst Med Res Fitzroy Vic 3065 Australia

Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.

关键词：血管紧张素ⅱ/代谢血管紧张素转换酶抑制药/药理学体重/药物作用缓激肽/代谢心脏扩大/并发症心脏扩大/病理学环GMP/尿药物协同作用吲哚类/药理学心肌梗死/并发症心肌梗死/代谢心肌梗死/病理学心肌梗死/病理生理学脑啡肽酶/拮抗剂和抑制剂肽基二肽酶A/血液培哚普利钾/尿蛋白酶抑制药/药理学放射免疫测定大鼠 Sprague-Dawley 肾素/血液钠/尿硫甲基氧代苯丙甘氨酸/类似物和衍生物硫甲基氧代苯丙甘氨酸/药理学动物男(雄)性大鼠

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Apoptosis of lung epithelial cells in response to TNF-α requires angiotensin II generation de novo

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期185卷 253-259页

作者： Wang, RQ Alam, G Zagariya, A Gidea, C Pinillos, H Lalude, O Choudhary, G Oezatalay, D Uhal, BD Michigan State Univ Dept Physiol E Lansing MI 48824 USA Michael Reese Hosp & Med Ctr Dept Med Chicago IL 60616 USA Michael Reese Hosp & Med Ctr Div Neonatol Chicago IL 60616 USA Michael Reese Hosp & Med Ctr Cardiovasc Inst Chicago IL 60616 USA

Recent work from this laboratory demonstrated that apoptosis of pulmonary alveolar epithelial cells (AEC) in response to fas requires angiotensin II (ANGII) generation de novo and binding to its receptor (Wang et at., 1999b, Am I Physiol Lung Cell Mol Physiol 277:L1245-L1250). These findings led us to hypothesize that a similar mechanism might be involved in the induction of AEC apoptosis by TNF-alpha. Apoptosis was detected by assessment of nuclear and chromatin morphology, increased activity of caspase 3, binding of annexin V, and by net cell loss inhibitable by the caspase inhibitor ZVAD-fmk. Purified human TNF-alpha induced dose-dependent apoptosis in primary type II pneumocytes isolated from rats or in the AEC-derived human lung carcinoma cell line A549. Apoptosis in response to TNF-alpha was inhibited in a dose-dependent manner by the nonselective ANGII receptor antagonist saralasin or by the nonthiol ACE inhibitor lisinopril;the inhibition of TNF-induced apoptosis was maximal at 50 mu g/ml saralasin (101% inhibition) and at 0.5 mu g/ml lisinopril (86% inhibition). in both cell culture models, purified TNF-alpha caused a significant increase in the mRNA for angiotensinogen (ANGEN), which was not expressed in unactivated cells. Transfection of primary cultures of rat AEC with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of TNF-stimulated apoptosis by 72% (P < 0.01). Exposure to TNF-alpha increased the concentration of ANGII in the serum-free extracellular medium by fivefold in A549 cell cultures and by 40-fold in primary AEC preparations;further, exposure to TNF-alpha for 40 h caused a net eel I loss of 70%, which was completely abrogated by either the caspase inhibitor ZVAD-fmk, lisinopril, or saralasin. Apoptosis in response to TNF-alpha was also completely inhibited by neutralizing antibodies specific for ANGII (P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the

关键词：血管紧张素Ⅱ/生物合成血管紧张素ⅱ/代谢血管紧张素转换酶抑制药/药理学血管紧张素原/遗传学血管紧张素原/代谢细胞凋亡/药物作用细胞凋亡/生理学细胞系剂量效应关系药物上皮细胞/药物作用上皮细胞/生理学基因表达/生理学赖诺普利/药理学肺/细胞学肺/药物作用肺/生理学蛋白质加工转译后/生理学 RNA 信使/代谢受体血管紧张素/拮抗剂和抑制剂受体血管紧张素/代谢沙拉新/药理学肿瘤坏死因子α/药理学人类

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拉萨(3658米)地区人体肾素活性、血管紧张Ⅱ及醛固酮的变化

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高原医学杂志 1986年第1期 23-28页

作者：雷淑贞西藏军区总医院

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Vascular response to angiotensin II is exaggerated through an upregulation of AT1 receptor in AT2 knockout mice

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第1期258卷 194-198页

作者： Tanaka, M Tsuchida, S Imai, T Fujii, N Miyazaki, H Ichiki, T Naruse, M Inagami, T Tokyo Womens Med Univ Dept Med Inst Clin Endocrinol Shinjuku Ku Tokyo 1628666 Japan Vanderbilt Univ Sch Med Dept Biochem Nashville TN 37232 USA Vanderbilt Univ Sch Med Dept Pediat Nashville TN 37232 USA Univ Tsukuba Inst Appl Biochem Gene Expt Ctr Tsukuba Ibaraki 305 Japan

Blood pressure is elevated and presser response to angiotensin II (Ang II) is exaggerated in AT2 null mice. The purpose of the present study was to elucidate the mechanism for the increased responsiveness to Ang II in the mice. The contraction of aortic strips generated by Ang II was significantly greater in the AT2 gene-deleted mice than the control, which was completely abolished by AT1 antagonist losartan, The aortic content of AT1 receptor was significantly increased (P < 0.05, n = 5) in the AT2 null mice (212 +/- 58.2 fmol/mg protein) compared with the control (98.2 +/- 55.9 fmol/mg protein). While both AT1 and AT2 mRNAs were expressed in the aorta of the control mice, only AT1 mRNA was expressed in the AT2 knockout mice. The expression of AT1 mRNA in the AT2 knockout mice was significantly higher (1.5-fold, P < 0.05, n = 5) than that in the control. The present study clearly demonstrated that the increased vascular reactivity to Ang II in AT2 knockout mice is at least partly due to an increased vascular AT1 receptor expression and suggested that AT2 counteracts AT1-mediated vascular action of Ang II through downregulation of AT1 receptor by a crosstalk between these receptors by some as yet unknown mechanisms. (C) 1999 Academic Press.

关键词：醛固酮/血液血管紧张素Ⅰ/代谢血管紧张素Ⅱ/遗传学血管紧张素ⅱ/代谢血管紧张素Ⅱ/药理学主动脉/药物作用主动脉/生理学碱基序列结合竞争性 DNA引物小鼠近交C57BL 小鼠基因敲除肌收缩/药物作用蛋白质结合受体血管紧张素/代谢逆转录聚合酶链反应动物男(雄)性小鼠

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Role of the His273 located in the sixth transmembrane domain of the angiotensin II receptor subtype AT2 in ligand-receptor interaction

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第3期257卷 704-707页

作者： Turner, CA Cooper, S Pulakat, L Bowling Green State Univ Dept Sci Biol Bowling Green OH 43403 USA

Angiotensin II receptor subtypes AT1 and AT2 are proteins with seven transmembrane domain (TMD) topology and share 34% homology. It was shown that His256, located in the sixth TMD of the AT1 receptor, is needed for the agonist activation by the Phe8 side chain of angiotensin II, although replacing this residue with arginine or glutamine did not significantly alter the affinity binding of the receptor. We hypothesized that the His273 located in the sixth transmembrane domain of the AT2 receptor may play a similar role in the functions of the AT2 receptor, although this residue was not identified as a conserved residue in the initial homology comparisions. Therefore, we replaced His273 of the AT2 receptor with arginine or glutamine and analyzed the ligand-binding properties of the mutant receptors using Xenopus oocytes as an expression system. Our results suggested that the AT2 receptor mutants His273Arg and His273 Glu have lost their affinity to [(125)I-Sar(1)-Ile(8)]Ang II, a peptidic ligand that binds both the AT1 and AT2 receptors and to (125)I-CGP42112A, a peptidic ligand that binds specifically to the AT2 receptor. Thus, His273 located in the sixth TMD of the AT2 receptor seems to play an important role in determining the binding properties of this receptor. Moreover, these results along with our previous observation that the Lys215 located in the 5th TMD of the AT2 receptor is essential for its high affinity binding to [(125)I-Sar(1)-Ile(8)]Ang II indicate that key amino acids located in the 5th and 6th TMDs of the AT2 receptor are needed for high affinity binding of the AT2 to its ligands. (C) 1999 Academic Press.

关键词：氨基酸取代血管紧张素Ⅱ/类似物和衍生物血管紧张素ⅱ/代谢结合部位细胞膜/代谢组氨酸/遗传学组氨酸/代谢配体赖氨酸/遗传学赖氨酸/代谢寡肽类/代谢卵母细胞/代谢 RNA 信使/投药和剂量 RNA 信使/遗传学受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/化学受体血管紧张素/遗传学受体血管紧张素/代谢沙拉新构效关系爪蟾光滑动物大鼠

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