Nature and severity of the glomerular response to nephron reduction is strain-dependent in mice

Nephron reduction Is an important factor in the development of glomeruloscl erosis. In a study of the oligosyndactyly (Os) mutation that causes a conge nital 50% reduction ill nephron number, we previously found that ROP Os/+ m ice developed glomerulosclerosis whereas C57B1/6J Os/+ mice did not, We con cluded that the predisposition to glomerulosclerosis depended largely on th e genetic background, the ROP being sclerosis-prone whereas the C57 strain was sclerosis-resistant, In the current experiments we asked whether the in tensity of the sclerotic response to nephron reduction In the ROP strain wa s 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 cau sed by a higher threshold for the induction of a sclerotic response In C57 mice. We further examined the relationship between glomerular hypertrophy a nd sclerosis. C57 +/+, C57 Os/+, ROP +/+, and ROP Os/+ mice were uninephrec tomized (NX) at age 10 weeks and followed for 8 weeks. We found no scleroti c changes in NX C57 +/+ and C57 Os/+ mice, despite a 75% reduction in nephr on 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, Exam ination 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, suggesti ng that the timing of nephron reduction affected the amplitude of the scler otic response in this strain, Following NX, an increase in glomerular volum e was found in C57 +/+, ROP +/+, and ROP Os/+ mice, However, NX did clot le ad to a further increase in glomerular volume in C57 Os/+ mice. We make thr ee conclusions: 1) sclerosis was more severe in the ROP strain when nephron reduction occurred In utero; 2) the absence of glomerulosclerosis in C57 m ice was not related to a higher threshold for a sclerosis response in this strain; and 3) whereas glomerular size continued to increase as nephron num ber decreased in ROP mice, it reached a plateau in C57 mice.