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Inflammation drives renal scarring in experimental pyelonephritis.

ABSTRACT: Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis. The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden. Transcriptome analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis. The integration of histopathology, quantification of cellular immune influx, and unbiased transcriptional profiling begins to define potential mechanisms of tissue injury during pyelonephritis in the context of an intact immune response. The clear relationship between inflammatory cell recruitment and fibrosis supports the hypothesis that acquired renal scarring arises as a consequence of excessive host inflammation and suggests that immunomodulatory therapies should be investigated to reduce renal scarring in patients with pyelonephritis.

SUBMITTER: Li B

PROVIDER: S-EPMC5283888 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Inflammation drives renal scarring in experimental pyelonephritis.

Li Birong B Haridas Babitha B Jackson Ashley R AR Cortado Hanna H Mayne Nicholas N Kohnken Rebecca R Bolon Brad B McHugh Kirk M KM Schwaderer Andrew L AL Spencer John David JD Ching Christina B CB Hains David S DS Justice Sheryl S SS Partida-Sanchez Santiago S Becknell Brian B

American journal of physiology. Renal physiology 20161019 1

Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia co ...[more]

PMID: 27760770

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Project description:BackgroundAcute pyelonephritis (APN), an acute and severe kidney infection, is usually treated with antibiotics. However, APN treatment has become increasingly challenging because of bacterial resistance. Adiponectin, an adipokine, has recently been reported to exhibit profound anti-inflammatory and anti-apoptotic effects. However, the effect of adiponectin on the outcomes of APN treatment remains unclear. In this study, we aimed to investigate the effects of adiponectin on APN and the mechanisms underlying these effects.MethodsWild-type C57 mice and adiponectin-knockout (KO) mice were divided into 6 groups: the wild-type control group, the wild-type model group, the wild-type adiponectin intervention group, the KO control group, the KO model group, and the adiponectin-KO intervention group. We measured white blood cell (WBC) and neutrophil counts (NC) using a multispecies hematology analyzer; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) using enzyme-linked immunosorbent assay (ELISA); blood urea nitrogen (BUN) and serum creatinine (SCr) levels using colorimetry; and the protein levels of JAK2, STAT3, p-JAK2, p-STAT3, Bcl-2, and Bax in renal tissues using western blot analysis. Apoptotic cells were detected using the transferase-mediated dUTP nick end labelling (TUNEL) assay.ResultsCompared to the wild-type mice, the KO mice showed a more severe inflammatory response and kidney damage after Escherichia coli infection. After treatment with exogenous adiponectin injection, the inflammatory response, oxidative stress, and kidney damage were partly alleviated. Adiponectin KO led to JAK2/STAT3 signaling activation, and exogenous adiponectin administration inactivated JAK2/STAT3 signaling in the APN model. APN can lead to an increase in the level of the protein Bax and a decrease in the level of the bcl-2 protein, thereby increasing apoptosis; this effect was inhibited by adiponectin.ConclusionsThrough use of a pyelonephritis mouse model, we demonstrated that adiponectin might alleviate renal cell apoptosis and inflammatory response by inactivating the JAK2/STAT3 signaling pathway.

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.

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Inflammation drives renal scarring in experimental pyelonephritis.

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Inflammation drives renal scarring in experimental pyelonephritis.

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