The lack of a functional p21(WAF1/CIP1) gene ameliorates progression to chronic renal failure

Abstract

Partial renal ablation leads to progressive renal insufficiency and is a model of chronic renal failure from diverse causes. We find that mice develop functional and morphologic characteristics of chronic renal failure after partial renal ablation, including glomerular sclerosis, systemic hypertension, and reduced glomerular filtration. However, we now report that littermates with a homozygous deletion of the gene for the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1), do not develop chronic renal failure after ablation. The markedly different reactions of the p21(+/+) and p21(-/-) animals was not because of differences in glomerular number or degree of renal growth but rather because of the presence or absence of a normal p21 gene. Although the reaction to the stress of renal ablation is both hyperplastic and hypertrophic in the presence of a functional p21 gene, it would appear that the absence of the p21 gene may induce a more hyperplastic reaction because proliferating-cell nuclear antigen expression, a marker of cell-cycle progression, in the renal epithelium of the remnant kidney was more than five times greater in the p21(-/-) mice than in the p21(+/+) animals. Because p21 is a potent inhibitor of the cell cycle, we speculate that p21 regulates the balance between hyperplasia and hypertrophy after renal ablation. We propose that this change in response inhibits the development of chronic renal failure. These studies suggest that controlling p21 function may ameliorate or even prevent progressive end-stage renal disease.

Figure 1

Renal function after ablation. Clearance of inulin (ml per minute) was calculated per gram kidney in mice from both genotypes. Statistically significant differences were only noted between the two populations at 14–16 weeks after ablation (P = 0.04). Values represent mean ± SE.

Figure 2

Mean arterial pressure. Mean systolic blood pressure was obtained by catheterizing the left femoral artery. Statistically significant differences between the two populations was noted as early as 6–8 weeks after ablation (P = 0.005), which increased by 14–16 weeks after ablation (P = 0.00002). Values represent mean ± SE.

Figure 3

Histologic changes in remnant kidney after ablation. Representative sections from either untreated (A and B), 8 weeks (C and D), 16 weeks (E), or 26 weeks (F) after ablation of wild-type (A, C, and E) or p21(−/−) (B, D, and F) mice. Magnification, ×390. Sections were stained with periodic acid/Schiff reagent.

Figure 4

Detection of interstitial fibrosis by using trichrome stain in remnant kidney after ablation. Representative sections from either 6 weeks (A) or 26 weeks (B) after ablation of wild-type (A) or p21(−/−) (B) mice. Magnification, ×390.

Figure 5

In situ hybridization for localization of p21 mRNA in remnant kidney cells after partial renal ablation. Hybridization of an antisense p21 probe to RNA in cells of remnant kidney 4 weeks (A) and 14 weeks (B) after ablation. Magnification, ×390.

Figure 6

Cell cycle analysis in remnant kidney cells after partial renal ablation. Immunodetection of nuclear PCNA localization 2 weeks after ablation in kidney sections from p21(−/−) (A) and wild-type (B) mice. Magnification, ×390.