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TGF?1 orchestrates renal fibrosis following Escherichia coli pyelonephritis.

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 TGF?1 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 TGF?1 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 TGF?1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGF?1 signaling cascade, leading to increases in cortical populations of MSC-like cells and the Gli1 + activated myofibroblasts that are responsible for scarring.

SUBMITTER: Hreha TN

PROVIDER: S-EPMC7104652 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis.

Hreha Teri N TN Collins Christina A CA Daugherty Allyssa L AL Twentyman Joy J Paluri Nitin N Hunstad David A DA

Physiological reports 20200301 6

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 ...[more]

PMID: 32227630

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Project description:We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection; consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis; a matching fraction of mice 1?month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5?months post-treatment; hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection.

Dataset Information

TGF?1 orchestrates renal fibrosis following Escherichia coli pyelonephritis.

Publications

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis.

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