Bruzzi I, Corna D, Zoja C, Orisio S, Schiffrin E L, Cavallotti D, Remuzzi G, Benigni A
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Am J Pathol. 1997 Nov;151(5):1241-7.
Experimental and human proteinuric glomerulopathies are associated with tubulo-interstitial injury that correlates with the decline of renal function even better than glomerular lesions do. Mechanism(s) leading to tubulo-interstitial damage are unknown. It has been proposed that excessive reabsorption of filtered proteins activates renal cells to produce vasoactive and inflammatory molecules including endothelin-1. The aim of the present study was twofold: we first evaluated the cellular origin of excessive renal endothelin-1 production in the renal mass reduction model and then related endothelin-1 distribution to the development of kidney lesions. Four groups of renal mass reduction (n = 15) and four groups of control rats (n = 5) were studied at 7, 14, 21, and 28 days after surgery. Urinary proteins in renal mass reduction rats were comparable with controls at day 7 but became significantly higher thereafter. Renal mass reduction rats first developed tubulo-interstitial changes, which were already evident at day 14 in the majority of them. At 28 days, renal mass reduction rats also developed glomerulosclerosis. A parallel increase of renal endothelin-1 gene expression and synthesis of the corresponding peptide in renal mass reduction rats versus controls was observed from day 14. Nonradioactive in situ hybridization confirmed a pattern of endothelin-1 mRNA consistent with the distribution of lesions. At day 14, endothelin-1 staining was stronger in renal mass reduction than in control kidneys and mainly localized to the cytoplasm of tubular cells, whereas glomeruli were negative. At day 28, endothelin-1 expression further increased in renal mass reduction rats as compared with controls, and the staining was apparent also in glomeruli. Thus, in renal mass reduction, a progressive up-regulation of endothelin-1 occurs during the development of renal injury, that first involves the tubules and, only in a subsequent phase, the glomeruli.
实验性和人类蛋白尿性肾小球病与肾小管间质损伤相关，这种损伤与肾功能下降的相关性甚至比肾小球病变更好。导致肾小管间质损伤的机制尚不清楚。有人提出，滤过蛋白的过度重吸收会激活肾细胞，从而产生包括内皮素 -1 在内的血管活性和炎症分子。本研究的目的有两个：我们首先评估了肾质量减少模型中肾内内皮素 -1 过度产生的细胞来源，然后将内皮素 -1 的分布与肾脏病变的发展相关联。在手术后的第 7、14、21 和 28 天，对四组肾质量减少的大鼠（n = 15）和四组对照大鼠（n = 5）进行了研究。肾质量减少大鼠的尿蛋白在第 7 天时与对照组相当，但此后显著升高。肾质量减少大鼠首先出现肾小管间质变化，在第 14 天时，大多数大鼠的这种变化已经很明显。在第 28 天，肾质量减少大鼠也出现了肾小球硬化。从第 14 天起，观察到肾质量减少大鼠与对照大鼠相比，肾内皮素 -1 基因表达和相应肽的合成平行增加。非放射性原位杂交证实了内皮素 -1 mRNA 的模式与病变分布一致。在第 14 天，肾质量减少组的内皮素 -1 染色比对照肾脏更强，主要定位于肾小管细胞的细胞质，而肾小球为阴性。在第 28 天，与对照组相比，肾质量减少大鼠的内皮素 -1 表达进一步增加，并且在肾小球中也出现了明显的染色。因此，在肾质量减少的情况下，肾损伤发展过程中内皮素 -1 会逐渐上调，首先累及肾小管，仅在随后的阶段累及肾小球。
