Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice

Atsuhiro Ichihara, Fumiaki Suzuki, Tsutomu Nakagawa, Yuki Kaneshiro, Tomoko Takemitsu, Mariyo Sakoda, A. H.M. Nurun Nabi, Akira Nishiyama, Takeshi Sugaya, Matsuhiko Hayashi, Tadashi Inagami

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Abstract

Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy.

Original languageEnglish
Pages (from-to)1950-1961
Number of pages12
JournalJournal of the American Society of Nephrology
Volume17
Issue number7
DOIs
Publication statusPublished - 2006 Jul

ASJC Scopus subject areas

  • Nephrology

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    Ichihara, A., Suzuki, F., Nakagawa, T., Kaneshiro, Y., Takemitsu, T., Sakoda, M., Nurun Nabi, A. H. M., Nishiyama, A., Sugaya, T., Hayashi, M., & Inagami, T. (2006). Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. Journal of the American Society of Nephrology, 17(7), 1950-1961. https://doi.org/10.1681/ASN.2006010029