Abboud H E, Ou S L, Velosa J A, Shah S V, Dousa T P
J Clin Invest. 1982 Feb;69(2):327-36. doi: 10.1172/jci110456.
Histamine is known to have a profound effect on capillary permeability in nonrenal tissues and this effect is presumably mediated by cyclic (c)AMP. Because in our previous experiments we found that histamine stimulates cAMP accumulation in glomeruli (Torres, V. E., T. E. Northryn, R. M. Edwards, S. V. Shah, and T. P. Dousa. 1978. Modulation of cyclic nucleotides in isolated rat glomeruli. J. Clin. Invest.62: 1334.), we now explored whether this amine is formed in renal tissue, namely in glomeruli, and whether its renal metabolism is altered in experimental nephrosis induced by puromycin aminonucleoside (PA) in rats. In normal rats, histamine content was higher (Delta + 240%) in cortex than in medulla. In glomeruli isolated from renal cortex, histamine content was significantly higher (Delta + 260%) than in tubules. Incubation of isolated glomeruli with l-histidine resulted in a time-dependent increase of histamine content in glomeruli, but no change was found in tubules. The increase in glomerular histamine was blocked by the histidine decarboxylase inhibitor bromocresine. In rats with PA nephrosis induced by a single intraperitoneal injection of PA (15 mg/100 g body wt) urinary excretion of histamine was markedly increased (>Delta + 200%), but control rats did not differ from rats with PA nephrosis in urinary excretions of l-histidine and of creatinine. At the peak of proteinuria (day 9 after injection of PA) the plasma level of histamine was slightly elevated, and plasma histidine slightly decreased in animals that developed PA nephrosis. The content of histamine was markedly higher and the level of histidine was significantly lower in the renal cortex of PA-nephrotic rats as compared with controls; PA-nephrotic and control rats did not differ in the content of histidine and histamine in the liver. In addition, the content of histamine was higher in glomeruli isolated from PA-nephrotic rats; lesser difference was found in cortical tubules. The results further indicate that PA-nephrotic rats have higher content of histamine in the renal cortex, predominently in glomeruli with increased urinary histamine excretion. The elevated renal cortical histamine is not due to higher availability of histamine precursor l-histidine. Results thus show that glomeruli are a major site of intrarenal histamine synthesis and accumulation, and also suggest that abnormal renal metabolism of this amine in PA nephrosis may be related, as a cause or as a consequence, to the pathogenesis of this disease.
已知组胺对非肾组织的毛细血管通透性有深远影响，且这种影响可能是由环磷腺苷（cAMP）介导的。因为在我们之前的实验中发现组胺能刺激肾小球中cAMP的积累（托雷斯，V.E.，T.E.诺思林，R.M.爱德华兹，S.V.沙阿，和T.P.杜萨。1978年。分离的大鼠肾小球中环核苷酸的调节。《临床研究杂志》62:1334），所以我们现在探究这种胺是否在肾组织中形成，即是否在肾小球中形成，以及在嘌呤霉素氨基核苷（PA）诱导的大鼠实验性肾病中其肾脏代谢是否改变。在正常大鼠中，皮质中的组胺含量高于髓质（增加240%）。从肾皮质分离的肾小球中的组胺含量显著高于肾小管（增加260%）。用L-组氨酸孵育分离的肾小球会导致肾小球中组胺含量随时间增加，但在肾小管中未发现变化。肾小球中组胺的增加被组氨酸脱羧酶抑制剂溴甲酚绿阻断。在通过单次腹腔注射PA（15mg/100g体重）诱导PA肾病的大鼠中，组胺的尿排泄量显著增加（增加>200%），但对照组大鼠与PA肾病大鼠在L-组氨酸和肌酐的尿排泄方面没有差异。在蛋白尿高峰期（注射PA后第9天），发生PA肾病的动物血浆组胺水平略有升高，血浆组氨酸略有下降。与对照组相比，PA肾病大鼠肾皮质中的组胺含量显著更高，组氨酸水平显著更低；PA肾病大鼠和对照组大鼠肝脏中的组氨酸和组胺含量没有差异。此外，从PA肾病大鼠分离的肾小球中的组胺含量更高；在皮质肾小管中发现的差异较小。结果进一步表明，PA肾病大鼠肾皮质中的组胺含量更高，主要在肾小球中，且尿组胺排泄增加。肾皮质组胺升高并非由于组胺前体L-组氨酸的可用性增加。因此结果表明肾小球是肾内组胺合成和积累的主要部位，并且还表明在PA肾病中这种胺的异常肾脏代谢可能作为病因或结果与该疾病的发病机制有关。
