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.

Highlights

  • Urinary tract infection (UTI) affects millions of people worldwide, exerting substantial impact both economically and on quality of life

  • We demonstrate that renal fibrosis after experimental Uropathogenic Escherichia coli (UPEC) pyelonephritis is driven by TGFβ1 and enhanced by androgens

  • In other models of renal fibrosis following non-infectious insult, mesenchymal stem cell (MSC)-like cell populations residing in the kidney and recruited from circulating precursors become activated myofibroblasts after local exposure to TGFβ1, subsequently depositing extracellular matrix components around the injured area that form a scar (Humphreys, 2018; Meng, Nikolic-Paterson, & Lan, 2016)

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Summary

| INTRODUCTION

Urinary tract infection (UTI) affects millions of people worldwide, exerting substantial impact both economically and on quality of life. A renal insult subsides and the secreted ECM is subsequently degraded by locally generated collagenases (Bauman et al, 2010; Wang et al, 2006; Zeisberg et al, 2003), enabling productive healing and regeneration of functional tubules in the affected area of kidney Aberrations in this signaling cascade, or more severe or prolonged injury, may push fibrotic signaling beyond the point of no return, precluding productive repair and resulting in permanent scarring (Genovese, Manresa, Leeming, Karsdal, & Boor, 2014). We extended these models into non-refluxing C57BL/6 mice, which when androgenized are permissive for pyelonephritis, but without the abscess formation seen in C3H mice (Olson et al, 2018) This system allowed us to interrogate the molecular mechanisms of renal fibrosis, separate from the severity of UTI per se, and to specify how the activity of these pathways is enhanced in the presence of androgens

| METHODS
| RESULTS
| DISCUSSION
Findings
Graphical Abstract

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