Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy

Masahiro Eriguchi, Mercury Lin, Michifumi Yamashita, Tuantuan V. Zhao, Zakir Khan, Ellen A. Bernstein, Susan B. Gurley, Romer A. Gonzalez-Villalobos, Kenneth E. Bernstein, Jorge F. Giani

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin- converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)F531-F542
JournalAmerican Journal of Physiology - Renal Physiology
Volume314
Issue number4
DOIs
StatePublished - Apr 2018

Keywords

  • Angiotensin-converting enzyme
  • Glomerular hyperfiltration
  • Megalin
  • Microalbuminuria
  • Tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Eriguchi, M., Lin, M., Yamashita, M., Zhao, T. V., Khan, Z., Bernstein, E. A., Gurley, S. B., Gonzalez-Villalobos, R. A., Bernstein, K. E., & Giani, J. F. (2018). Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy. American Journal of Physiology - Renal Physiology, 314(4), F531-F542. https://doi.org/10.1152/ajprenal.00523.2017