Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli

Zhong Gao Xu, Tae Hyun Yoo, Dong Ryeol Ryu, Hyeong Cheon Park, Sung Kyu Ha, Dae Suk Han, Sharon G. Adler, Rama Natarajan, Shin Wook Kang

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67 Citations (Scopus)


Background. Diabetic nephropathy is characterized by glomerular and tubular hypertrophy, and angiotensin II receptor blockers (ARBs) are known to prevent renal hypertrophy in diabetic patients. Methods. To determine the effect of ARB on podocyte p27Kip1 mRNA and protein expression, podocytes were exposed to 5.6 mmol/L normal glucose or 25 mmol/L high glucose with or without ARB, 10-7 mol/L L-158,809. For animal studies, streptozotocin-induced diabetic rats were left untreated or were treated with 1 mg/kg/day L-158,809 for 3 months (diabetes mellitus + ARB). Competitive reverse transcription- polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and morphometric analyses were performed. Results. p27Kip1 mRNA and protein expression in podocytes exposed to high glucose and in 3-month diabetic glomeruli were significantly increased (P < 0.01). High glucose significantly increased angiotensin II levels both in cell lysates and in media compared with normal glucose (P < 0.05) and exogenous angiotensin II also increased p27Kip1 mRNA and protein expression in podocytes. L-158,809 treatment in podocytes inhibited the increase in p27Kip1 mRNA expression by 84%, and protein expression by 89% (P < 0.05). p27Kip1 mRNA and protein expression in diabetic + ARB glomeruli were also significantly reduced by 78% and 85%, respectively, compared with diabetic glomeruli (P < 0.01). ARB treatment also significantly ameliorated increased glomerular p27 Kip1 expression in diabetes mellitus as assessed by immunohistochemistry (P < 0.01). The increase in glomerular volume in diabetes mellitus was also inhibited by 81% with ARB treatment (P < 0.05). Conclusion. p27Kip1 mRNA and protein expression were increased in diabetic glomeruli as well as in high glucose-stimulated podocytes, and this increment in p27Kip1 expression was ameliorated by ARB treatment. These findings indicate that ARB treatment has an additional effect on preventing renal hypertrophy in diabetes mellitus.

Original languageEnglish
Pages (from-to)944-952
Number of pages9
JournalKidney International
Issue number3
Publication statusPublished - 2005 Mar

Bibliographical note

Funding Information:
This work was supported in part by the BK21 (Brain Korea 21) Project for Medical Sciences, Yonsei University and by the Yonsei University College of Medicine, Internal Medicine Research Grant for 2002 (to H.C.P.), and grants from the Juvenile Diabetes Research (to S.G.A. and R.N.) and the National Institutes of Health (R01-DK58191) (to R.N.). The authors are thankful to Dr. Peter Mundel (Albert Einstein College of Medicine, Bronx, NY) for kindly providing us with the immortalized mouse podocyte cell line and to Merck Sharp and Dohme, Korea, for the generous supply of L-158,809.

All Science Journal Classification (ASJC) codes

  • Nephrology


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