UT-A1/A3 knockout mice show reduced fibrosis following unilateral ureteral obstruction

Fitra Rianto, Akihiro Kuma, Carla L. Ellis, Faten Hassounah, Eva L. Rodriguez, Xiaonan H. Wang, Jeff M. Sands, Janet D. Klein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-β, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-β, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson's trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.

Original languageEnglish (US)
Pages (from-to)F1160-F1166
JournalAmerican Journal of Physiology - Renal Physiology
Volume318
Issue number5
DOIs
StatePublished - May 2020
Externally publishedYes

Keywords

  • Chronic kidney disease
  • Unilateral ureteral obstruction
  • Urea transporter-A1
  • Urea transporter-A3

ASJC Scopus subject areas

  • Physiology
  • Urology

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