TY - JOUR
T1 - Inflammation drives renal scarring in experimental pyelonephritis
AU - Li, Birong
AU - Haridas, Babitha
AU - Jackson, Ashley R.
AU - Cortado, Hanna
AU - Mayne, Nicholas
AU - Kohnken, Rebecca
AU - Bolon, Brad
AU - McHugh, Kirk M.
AU - Schwaderer, Andrew L.
AU - Spencer, John David
AU - Ching, Christina B.
AU - Hains, David S.
AU - Justice, Sheryl S.
AU - Partida-Sanchez, Santiago
AU - Becknell, Brian
N1 - Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017
Y1 - 2017
N2 - 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 ischemiareperfusion 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.
AB - 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 ischemiareperfusion 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.
KW - Fibrosis
KW - Inflammation
KW - Mucosal injury
KW - Pyelonephritis
KW - Urinary tract infection
KW - Vesicoureteral reflux
UR - http://www.scopus.com/inward/record.url?scp=85008394017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85008394017&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00471.2016
DO - 10.1152/ajprenal.00471.2016
M3 - Article
C2 - 27760770
AN - SCOPUS:85008394017
SN - 0363-6127
VL - 312
SP - F43-F53
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 1
ER -