The cyclin kinase inhibitor p21(WAF1/CIP1) is required for glomerular hypertrophy in experimental diabetic nephropathy

Mouhannad Al-Douahji, James Brugarolas, Paul A J Brown, Catherine O. Stehman-Breen, Charles E. Alpers, Stuart J. Shankland

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Background. Diabetic nephropathy is characterized by glomerular hypertrophy. We have recently shown that experimental diabetes mellitus is associated with an increase in glomerular expression of the cyclin kinase inhibitor p21(WAF1/CIP1) (p21). Furthermore, in vitro glucose-induced mesangial cell hypertrophy is also associated with an up-regulated expression of p21. In this study, we tested the hypothesis that p21 mediates diabetic glomerular hypertrophy in vivo. Methods. Experimental diabetes mellitus was induced by streptozotocin in mice in which p21 was genetically deleted (p21 - /-) and in wild-type mice (p21 +/+). Kidney biopsies were obtained from diabetic and control (citrate injected) p21 +/+ and p21 -/- mice at day 60. The tissue was used for morphologic studies of glomerular size (measured by computer image-analysis system), glomerular cellularity (cell count), glomerular matrix expansion (silver stain), apoptosis (TUNEL), and expression of transforming growth factor-β1 (TGF-β1) by in situ hybridization. Results. The glomerular tuft area increased 11.21% in diabetic p21 +/+ mice at day 60 compared with control (3329.98 ± 244.05 μm2 vs. 2994.39 ± 176.22 μm2, P = 0.03), and the glomerular cell count did not change in diabetic p21 +/+ mice at day 60 compared with the control. These findings are consistent with glomerular hypertrophy. In contrast, the glomerular tuft area did not increase in diabetic p21 -/- mice at day 60 compared with the control (3544.15 ± 826.49 vs. 3449.15 ± 109.65, P = 0.82), nor was there an increase in glomerular cell count (41.41 ± 13.18 vs. 46.95 ± 3.00, P = 0.43). Diabetic p21 +/+ mice, but not p21 -/- mice, developed an increase in proteinuria at day 60 compared with the control. Tubular cell proliferation, measured by proliferating cell nuclear antigen immunostaining, was increased in both diabetic p21 +/+ (2.1-fold) and p21 -/- (7.61-fold) mice compared with controls. Glomerular cell apoptosis did not increase in diabetic mice. Although glomerular TGF-β1 mRNA levels increased in both strains of diabetic mice at day 60, the glomerular matrix did not expand. Conclusions. Hyperglycemia was associated with glomerular hypertrophy in p21 +/+ mice. Despite the increase in TGF-β1 mRNA, diabetic p21 -/- mice did not develop glomerular hypertrophy, providing evidence that the cyclin kinase inhibitor p21 may be required for diabetic glomerular hypertrophy induced by TGF-β1. The loss of p21 increases tubular but not glomerular cell proliferation in diabetic nephropathy. The absence of glomerular hypertrophy appears protective of renal function in diabetic mice.

Original languageEnglish (US)
Pages (from-to)1691-1699
Number of pages9
JournalKidney international
Volume56
Issue number5
DOIs
StatePublished - Jan 1 1999

Keywords

  • Cyclin
  • Diabetes
  • Glomerulus
  • Hypertrophy
  • P21
  • Proliferation

ASJC Scopus subject areas

  • Nephrology

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