Pyelonephritis-Mediated Renal Fibrosis is Associated with Severe Inflammation. Mus musculus

Despite a growing body of knowledge regarding the pathogenesis of urinary tract infection, the mechanisms of renal scaring associated with acute pyelonephritis (APN) are poorly understood. Limited data available regarding histopathology, immune cell recruitment and gene expression changes during APN severely restricts the development of therapies to prevent renal scars. Here, we address this knowledge gap using inbred, immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli leads to renal mucosal injury, tubulointerstitial nephritis, and interstitial fibrosis – all histopathologic features of human APN. Interstitial fibrosis correlates most significantly with inflammation 7 and 28 days post infection. Flow cytometry identifies recruitment of neutrophils, macrophages, and lymphocytes to infected kidneys. Renal transcriptional analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. Thus, C3H/HeOuJ mice with APN comprise a novel model of renal fibrosis that recapitulates the human condition of acquired renal scarring in an immunocompetent setting. The integration of organ pathology, quantitative cellular immune influx, and transcriptional analyses begin, for the first time, to define mechanisms of tissue injury during APN in the context of an intact immune response. The strong relationship between pro-inflammatory cell recruitment and fibrosis supports the hypothesis that renal scarring arises as a consequence of excessive host inflammation. Our studies suggest that immunomodulatory therapies should be investigated to reduce renal scarring in patients with APN. Overall design: Gene expression was measured at baseline (n=4) and 7 days (n=4) post infection in kidneys of adult female C3H/HeOUJ mice.