A marked deficiency in circulating and renal IGF-I peptide does not inhibit compensatory renal enlargement in uninephrectomized mice

Abstract

Objective: Increase in kidney IGF-I levels due to its increased trapping from the circulation was hypothesized to be a key mediator of compensatory renal enlargement. We tested this hypothesis using genetically engineered mice with extremely low circulating IGF-I levels.

Design: Both IGF-I deficient (ID) and normal (N) mice underwent a uninephrectomy (UNx) and sacrificed 2 or 9days later.

Results: Initial body weight (BW) and kidney weight (KW) were significantly reduced in ID vs. N mice, while KW/BW ratios were similar. KW increased post-UNx to a comparable extent in ID and N mice (125±4 and 118±6% of pre-UNx KW, p<0.05 vs. C). Kidney IGF-I mRNA levels were similar in the ID and N mice and did not change post-UNx. Kidney IGF-I peptide levels pre-UNx were significantly lower in ID vs. N mice (25±5 vs. 305±39ng/g) and increased in both groups after UNx, remaining low in ID mice (45±4 in ID vs 561±64ng/g in N). IGF type 1 receptor phosphorylation was unchanged.

Conclusion: While a severe deficiency of circulating IGF-I impairs body growth, UNx induces a significant and proportional increase in renal mass in ID mice despite markedly decreased kidney IGF-I levels (>90% reduction) and no significant change in receptor phosphorylation. This all suggests that factors other than circulating and locally produced IGF-I are responsible for compensatory renal enlargement.

Fig. 1

(a) Body weight, (b) Pre-UNx (left) kidney weight, and (c) serum IGF-I levels are severely reduced in serum IGF-deficient (ID) mice compared to normal control (N) mice. * p<0.001.

Fig. 2

Two days post-UNx, KW increased significantly vs pre-UNx values (2b): there was an average increase of 8 and 19 mg in ID and N mice respectively (p<0.05). However, the percent of KW increase (a) and KW/BW ratio (mg/g) (b) were similar between strains, 2 and 9 days following UNx. Values with a non-identical letters above bars are different (p<0.05). Values with common letters do not differ from each other.

Fig. 3

Kidney IGF-I mRNA levels (depicted as percentage of pre-UNx N group) were similar in N and ID mice and did not change following UNx. Values with common letters above bars do not differ from each other.

Fig. 4

(a) Two days following UNx, kidney IGF-I peptide concentration increased by 256 ng/g in N mice and by 20 ng/g in ID mice. (b) A similar trend was seen on Day 9. * p<0.05 when Post- vs. pre-UNx are compared. ^# p<0.05 when N vs. ID are compared.

Fig. 5

Kidney IGF type 1 receptor (IGF1R) (total and phosphorylated fraction). Representative Western immunoblots of normal (N) (upper panel) and IGF-I deficient (ID) (lower panel) mice, pre-and 2 days post-UNx. Levels of IGF1R protein (MW ~90 KD) and its phosphorylated fraction (pIGF1R) are unaltered. Kidney lysates were subjected directly to Western immunoblot analysis, first with an anti-phosphorylated IGF-I/Insulin receptor antibody, then stripped and reblotted with an anti IGF-I receptor antibody.