PATHO-PHYSIOLOGY OF CHRONIC TUBULO-INTERSTITIAL DISEASE IN RATS - INTERACTIONS OF DIETARY ACID LOAD, AMMONIA, AND COMPLEMENT COMPONENT-C3
PATHO-PHYSIOLOGY OF CHRONIC TUBULO-INTERSTITIAL DISEASE IN RATS - INTERACTIONS OF DIETARY ACID LOAD, AMMONIA, AND COMPLEMENT COMPONENT-C3
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DOI：
10.1172/jci112020
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发表时间：
1985-01-01
影响因子：
15.9
通讯作者：
HOSTETTER, TH
中科院分区：
文献类型：
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作者：
NATH, KA;HOSTETTER, MK;HOSTETTER, TH
人类终末期肾脏及其实验类似物（大鼠的残余肾脏）表现出广泛的肾小管间质疾病。研究了这种肾小管间质损伤的发病机制，以确定它是否依赖于肾小管功能的适应性变化，特别是当肾质量减少时氨产生的适应性变化。通过膳食补充碳酸氢钠 (NaHCO3)，1 3/4 肾切除大鼠的膳食酸负荷降低，而对照大鼠（在 1 3/4 肾切除术后血清肌酐配对）则补充等摩尔 NaCl。 4-6周后，补充NaHCO3的大鼠表现出肾小管功能损伤较少，通过尿总蛋白排泄率和低MW蛋白测量，对氨基马尿酸/单位肾小球滤过率的转运最大值较高，肾小管间质损伤的组织学证据较少，补体成分C3和C5b-9的沉积较少，肾静脉总氨浓度较低。肾小管功能的这种差异不能简单地根据全身碱化来解释，肾小管损伤的差异也不能归因于肾小球功能的差异。因为氨等 N 亲核试剂与 C3 反应形成补体旁路转化酶，并且因为组织中氨水平的增加与肾小管间质损伤的增加有关，所以肾内氨水平的增加显然是有害的，因为补体旁路的激活。由此产生趋化和溶细胞补体成分，导致肾小管间质炎症。补充碱可减少大鼠残肾中的慢性肾小管间质疾病，这似乎至少部分是由于皮质氨的减少及其与替代补体途径的相互作用所致。
The human end-stage kidney and its experimental analog, the remnant kidney in the rat, exhibit widespread tubulo-interstitial disease. The pathogenesis of such tubulo-interstitial injury was studied to determine if it is dependent upon adaptive changes in tubular function and, in particular, in ammonia production when renal mass is reduced. Dietary acid load was reduced in 1 3/4-nephrectomized rats by dietary supplementation with sodium bicarbonate (NaHCO3), while control rats, paired for serum creatinine after 1 3/4 nephrectomy, were supplemented with equimolar NaCl. After 4-6 wk, NaHCO3-supplemented rats demonstrated less impairment of tubular function as measured by urinary excretory rates for total protein and low MW protein and higher transport maximum for para-aminohippurate/unit glomerular filtration rate, less histologic evidence of tubulo-interstitial damage, less deposition of complement components C3 and C5b-9, and a lower renal vein total ammonia concentration. Such differences in tubular function could not be accounted for simply on the basis of systemic alkalinization, and differences in tubular injury could not be ascribed to differences in glomerular function. Because N nucleophiles such as ammonia react with C3 to form a convertase for the alternative complement pathway, and because increased tissue levels of ammonia are associated with increased tubulo-interstitial injury, augmented intrarenal levels of ammonia are apparently injurious because of activation of the alternative complement pathway. Chemotactic and cytolytic complement components are thereby generated, leading to tubulo-interstitial inflammation. Alkali supplementation reduces chronic tubulo-interstitial disease in the remnant kidney of the rat, and this seemingly results, at least in part, from reduction in cortical ammonia and its interaction with the alternative complement pathway.