TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

Teri N. Hreha, Christina A. Collins, Allyssa L. Daugherty, Joy Twentyman, Nitin Paluri, David A. Hunstad

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Renal scarring after pyelonephritis is linked to long-term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti-androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post-infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)-like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non-androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC-like cells and the Gli1 + activated myofibroblasts that are responsible for scarring.

Original languageEnglish
Article numbere14401
JournalPhysiological Reports
Volume8
Issue number6
DOIs
StatePublished - Mar 1 2020

Keywords

  • Escherichia coli
  • TGFβ
  • fibrosis
  • pyelonephritis
  • renal scarring

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