Nature and Severity of the Glomerular Response to Nephron Reduction Is Strain-Dependent in Mice

Abstract

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. (Am J Pathol 1999, 154:891-897)Because the shortage of cadaver kidneys has prompted an increase in the use of kidneys from living donors for transplantation, 1 it is important to know whether this practice places donors at risk. 2-6 Many, 5,6 but not all, [2][3][4] retrospective studies have demonstrated that adult donors do not have a significant decline of renal function in follow-up periods of up to 45 years. It is possible that the risk to the donor depends on their susceptibility to a reduction in renal mass. In fact, patients undergoing unilateral nephrectomy who have a family history of renal disease and hypertension appear to carry a higher risk of long-term renal insufficiency than those without familial antecedents. 7 There is increasing evidence that genetic factors play an important role in the development of a large number of glomerular diseases. 8 -10 Furthermore, we recentl...

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

“…We did not observe any glomerular changes in obese B-db3J mice. This is not surprising due to the lack of overt hyperglycaemia in these mice and the classification of the C57BL/6J strain as being resistant to developing glomerulosclerosis [44,45] using a completely different genetic model. Our results are interesting because LEPR-deficient C57BLKS/J-db mice, the parent strain of the F-db and the B-db strains, are hyperglycaemic and show signs of diabetic nephropathy with alterations in functional measures such as creatinine clearance [46].…”

Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury

“…Indeed, recent works suggested that genetic factors influence the response to nephron reduction. Esposito et al (49) have shown recently that unilateral nephrectomy induced glomerulosclerosis in ROP, but not in C57BL/6 mice, whereas Kren and Hostetter (50) have reported that C57BL/6 mice were resistant to the devel-…”

Mouse Models of Diabetic Nephropathy

“…Studies of Os/ϩ ROP mice show that they possess approximately 50% fewer nephrons in the Os/ϩ mice than in the ϩ/ϩ mice (160). In general, wild-type mice (Os ϩ/ϩ , Ra ϩ/ϩ , and Pt ϩ/ϩ ) of ROP background seem to be more prone to glomerulosclerosis than C57BL/6 mice after a reduction in renal mass (161)(162)(163). Mice on the ROP background, in the absence of Os, Ra, or Pt mutant alleles, may also exhibit increased propensity for glomerulosclerosis after combined nephron mass reduction and diabetes (146).…”