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Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury

Authors
 Beom Jin Lim  ;  Jae Won Yang  ;  Jun Zou  ;  Jianyong Zhong  ;  Taiji Matsusaka  ;  Ira Pastan  ;  Ming-Zhi Zhang  ;  Raymond C. Harris  ;  Hai-Chun Yang  ;  Agnes B. Fogo 
Citation
 Kidney International, Vol.92(6) : 1395-1403, 2017 
Journal Title
 Kidney International 
ISSN
 0085-2538 
Issue Date
2017
Keywords
atubular glomeruli ; glomerular injury ; tubuloglomerular feedback ; tubulointerstitial fibrosis
Abstract
Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25+/DTR+, but not in Nep25+/DTR- mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25+/DTR+ than in DTR- mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25+/DTR+ than Nep25+/DTR- mice with more severe sclerosis in the tubule-connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/161353
DOI
10.1016/j.kint.2017.04.010
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실)
Yonsei Authors
임범진(Lim, Beom Jin)
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Full Text
https://www.sciencedirect.com/science/article/pii/S0085253817302831
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