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.

Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis

“…Ascension of uropathogens to the kidneys can lead to pyelonephritis, which, even with successful antibiotic treatment, may carry long-term repercussions for the patient, including the development of renal scarring, hypertension and eventual progression to end-stage renal disease ( Jacobson et al, 1989 ; Martinell et al, 1996 ; Wennerström et al, 2000 ; Levey and Coresh, 2012 ). Ascending bacterial infection of the renal parenchyma in humans elicits severe tubulointerstitial inflammation ( Goluszko et al, 1997 ; Svensson et al, 2005 , 2011 ; Mak and Kuo, 2006 ; Olson et al, 2016 ; Li et al, 2017 ). This innate inflammatory response, perhaps as much as bacterial processes per se , may largely underlie renal damage resulting from UTI, and is correlated with loss of functional renal tissue (scarring) and the development of fibrosis ( Miller and Phillips, 1981 ; Bille and Glauser, 1982 ; Anders and Schaefer, 2014 ; Suárez-Álvarez et al, 2016 ).…”

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

“…Tgfb1 transcription was increased in TC‐treated mice early in infection, with elevated TGFβ1 production observed in TC‐treated mice was most evident in epithelial cells, predominantly in the distal nephron, earlier in infection (up to 7 dpi) and then in non‐epithelial (CD45−, E‐cadherin−) cell types later in infection (7–28 dpi). This sequence is logical, as renal epithelial surfaces are likely contacted earliest by UPEC during ascending infection (Li et al, 2017; Olson et al, 2018). Thus, epithelial TGFβ1 signaling is likely the initiator of the fibrotic response to infection; in other models, TGFβ1 signaling from epithelial cells alone is sufficient to drive a fibrotic response to injury (Gentle et al, 2013; Olson et al, 2018).…”

Diverse Role of TGF-β in Kidney Disease

“…CKD eventually leads to the development of end-stage renal disease (ESRD) (Eddy and Neilson, 2006;Liu, 2011). Fibrosis and inflammation are the two major features of CKD and prolonged renal inflammation promotes renal fibrosis as well Li et al, 2017). Physiologically, fibrosis is a repair and healing process in response to the initial renal insults.…”