Secreted protein acidic and rich in cysteine (SPARC) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) increments by the renin-angiotensin system induce renal fibrosis in deoxycorticosterone acetate-salt hypertensive rats
Secreted protein acidic and rich in cysteine (SPARC) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) increments by the renin-angiotensin system induce renal fibrosis in deoxycorticosterone acetate-salt hypertensive rats
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肾素-血管紧张素系统增加富含半胱氨酸的酸性分泌蛋白 (SPARC) 和具有 1 型血小板反应蛋白基序的解整合素和金属蛋白酶 (ADAMTS1) 的增量，诱导醋酸去氧皮质酮盐高血压大鼠的肾纤维化
DOI：
10.1016/j.ejphar.2021.174681
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发表时间：
2022
影响因子：
5
通讯作者：
Nakata Tetsuo
中科院分区：
文献类型：
--
作者：
Toba Hiroe;Ikemoto Mitsushi J.;Kobara Miyuki;Nakata Tetsuo
分泌的富含半胱氨酸的酸性蛋白（ECM）是一种细胞外基质（ECM）蛋白，最近被证明通过在衰老心脏中产生具有血小板反应蛋白1型基序的去整合素和金属蛋白酶（ADAMTS 1）来诱导胶原沉积。ADAMTS 1通过降解ECM成分调节ECM周转，其过度活化有助于各种病理状态，包括纤维化。本研究使用单肾切除大鼠，用醋酸脱氧皮质酮（DOCA，40 mg/kg/周，皮下注射）和盐（1%饮用水）治疗，研究了肾脏纤维化中的病理生理学调节和ADAMTS 1的作用。在3周治疗期间，DOCA和盐的给药逐渐显著升高收缩压，诱导蛋白尿，降低肌酐清除率，并增加肾脏中NADPH氧化酶衍生的超氧化物产生、丙二醛浓度和单核细胞趋化蛋白-1和骨桥蛋白表达。肾小球硬化、纤维状胶原沉积和转化生长因子-β表达以时间依赖性方式增加，而ADAMTS和ADAMTS 1表达显示出与这些变化相似的模式。血管紧张素II 1型受体阻断剂氯沙坦抑制了肾脏成纤维细胞NRK-49 F中的ADAMTS 1和RIP 1的过度表达，并且体外暴露于血管紧张素II诱导了NRK-49 F细胞中RIP 1和ADAMTS 1的产生。用小干扰RNA敲低ADAMTS 1基因可减少ADAMTS 1表达的所有形式（110 kDa潜伏形式和87-和65-kDa生物活性形式）以及胶原蛋白的产生。这些结果表明，肾素-血管紧张素系统诱导的，并可能是一个纤维化的因素，至少部分，通过生产ADAMTS 1在高血压性肾脏疾病。
Secreted protein acidic and rich in cysteine (SPARC), an extracellular matrix (ECM) protein, was recently shown to induce collagen deposition through the production of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) in the aging heart. ADAMTS1 regulates ECM turnover by degrading ECM components, and its excessive activation contributes to various pathological states, including fibrosis. The present study investigated the pathophysiological regulation and role of SPARC and ADAMTS1 in renal fibrosis using uninephrectomized rats treated with deoxycorticosterone acetate (DOCA, 40 mg/kg/week, subcutaneously) and salt (1% in drinking water). The administration of DOCA and salt gradually and significantly elevated systolic blood pressure during the 3-week treatment period, induced proteinuria, decreased creatinine clearance, and increased NADPH oxidase-derived superoxide production, malondialdehyde concentrations, and monocyte chemoattractant protein-1 and osteopontin expression in the kidneys. Glomerulosclerosis, fibrillar collagen deposition, and transforming growth factor-β expression increased in a time-dependent manner, and SPARC and ADAMTS1 expression showed a similar pattern to these changes. The angiotensin II type-1 receptor blocker losartan suppressed the overexpression of SPARC and ADAMTS1, and anin vitroexposure to angiotensin II induced the production of both SPARC and ADAMTS1 in renal fibroblast NRK-49F cells. Knockdown of the SPARC gene with small interfering RNA reduced all forms (the 110-kDa latent and 87- and 65-kDa bioactive forms) of ADAMTS1 expression as well as collagen production. These results suggest that SPARC is induced by the renin-angiotensin system and may be a fibrogenic factor, at least in part, by producing ADAMTS1 in hypertensive renal disease.