Esposito C, He C J, Striker G E, Zalups R K, Striker L J
Division of Nephrology, IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
Am J Pathol. 1999 Mar;154(3):891-7. doi: 10.1016/S0002-9440(10)65336-9.
Nephron reduction is an important factor in the development of glomerulosclerosis. In a study of the oligosyndactyly (Os) mutation that causes a congenital 50% reduction in nephron number, we previously found that ROP Os/+ mice developed glomerulosclerosis whereas C57B1/6J Os/+ mice did not. We concluded that the predisposition to glomerulosclerosis depended largely on the genetic background, the ROP being sclerosis-prone whereas the C57 strain was sclerosis-resistant. In the current experiments we asked whether the intensity of the sclerotic response to nephron reduction in the ROP strain was related to the time at which it occurred, ie, a pre- or post-natal event. We also determined whether the absence of lesions in C57 Os/+ mice was caused by a higher threshold for the induction of a sclerotic response in C57 mice. We further examined the relationship between glomerular hypertrophy and sclerosis. C57 +/+, C57 Os/+, ROP +/+, and ROP Os/+ mice were uninephrectomized (NX) at age 10 weeks and followed for 8 weeks. We found no sclerotic changes in NX C57 +/+ and C57 Os/+ mice, despite a 75% reduction in nephron number in the latter. In contrast, both NX ROP +/+ and NX ROP Os/+ mice had glomerulosclerosis, which was more severe in the NX ROP Os/+ mice. Examination of extracellular matrix synthesis and degradation at the mRNA level revealed that synthesis exceeded degradation in ROP Os/+ mice. The lesions in NX ROP +/+ were less severe than in sham-operated ROP/Os mice, suggesting that the timing of nephron reduction affected the amplitude of the sclerotic response in this strain. Following NX, an increase in glomerular volume was found in C57 +/+, ROP +/+, and ROP Os/+ mice. However, NX did not lead to a further increase in glomerular volume in C57 Os/+ mice. We make three conclusions: 1) sclerosis was more severe in the ROP strain when nephron reduction occurred in utero; 2) the absence of glomerulosclerosis in C57 mice was not related to a higher threshold for a sclerosis response in this strain; and 3) whereas glomerular size continued to increase as nephron number decreased in ROP mice, it reached a plateau in C57 mice.
肾单位减少是肾小球硬化发展的一个重要因素。在一项关于导致先天性肾单位数量减少50%的少指（Os）突变的研究中，我们先前发现ROP Os/+小鼠会发生肾小球硬化，而C57B1/6J Os/+小鼠则不会。我们得出结论，肾小球硬化的易感性在很大程度上取决于遗传背景，ROP品系易患硬化，而C57品系具有抗硬化能力。在当前实验中，我们探究了ROP品系中对肾单位减少的硬化反应强度是否与其发生时间有关，即产前或产后事件。我们还确定了C57 Os/+小鼠无病变是否是由于C57小鼠诱导硬化反应的阈值较高所致。我们进一步研究了肾小球肥大与硬化之间的关系。在10周龄时对C57 +/+、C57 Os/+、ROP +/+和ROP Os/+小鼠进行单侧肾切除（NX），并随访8周。我们发现NX C57 +/+和C57 Os/+小鼠没有硬化改变，尽管后者的肾单位数量减少了75%。相比之下，NX ROP +/+和NX ROP Os/+小鼠均出现了肾小球硬化，其中NX ROP Os/+小鼠的硬化更为严重。在mRNA水平检测细胞外基质的合成与降解发现，ROP Os/+小鼠中合成超过了降解。NX ROP +/+小鼠的病变比假手术的ROP/Os小鼠轻，这表明肾单位减少的时间影响了该品系中硬化反应的幅度。NX后，在C57 +/+、ROP +/+和ROP Os/+小鼠中发现肾小球体积增加。然而，NX并未导致C57 Os/+小鼠的肾小球体积进一步增加。我们得出三个结论：1）当在子宫内发生肾单位减少时，ROP品系中的硬化更为严重；2）C57小鼠中无肾小球硬化与该品系中较高的硬化反应阈值无关；以及3）在ROP小鼠中，随着肾单位数量减少，肾小球大小持续增加，而在C57小鼠中则达到了稳定状态。
