Epidermal growth factor attenuates tubular necrosis following mercuric chloride damage by regeneration of indigenous, not bone marrow-derived cells.
To assess effects of epidermal growth factor (EGF) and pegylated granulocyte colony-stimulating factor (P-GCSF; pegfilgrastim) administration on the cellular origin of renal tubular epithelium regenerating after acute kidney injury initiated by mercuric chloride (HgCl2 ). Female mice were irradiated and male whole bone marrow (BM) was transplanted into them. Six weeks later recipient mice were assigned to one of eight groups: control, P-GCSF+, EGF+, P-GCSF+EGF+, HgCl2 , HgCl2 +P-GCSF+, HgCl2 +EGF+ and HgCl2 +P-GCSF+EGF+. Following HgCl2 , injection tubular injury scores increased and serum urea nitrogen levels reached uraemia after 3 days, but EGF-treated groups were resistant to this acute kidney injury. A four-in-one analytical technique for identification of cellular origin, tubular phenotype, basement membrane and S-phase status revealed that BM contributed 1% of proximal tubular epithelium in undamaged kidneys and 3% after HgCl2 damage, with no effects of exogenous EGF or P-GCSF. Only 0.5% proximal tubular cells were seen in S-phase in the undamaged group kidneys; this increased to 7-8% after HgCl2 damage and to 15% after addition of EGF. Most of the regenerating tubular epithelium originated from the indigenous pool. BM contributed up to 6.6% of the proximal tubular cells in S-phase after HgCl2 damage, but only to 3.3% after additional EGF. EGF administration attenuated tubular necrosis following HgCl2 damage, and the major cause of this protective effect was division of indigenous cells, whereas BM-derived cells were less responsive. P-GCSF did not influence damage or regeneration.
Department of Nephrology and Division of Clinical Toxicology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Linkou, Taiwan; Histopathology Laboratory, Cancer Research UK, London Research Institute, London, UK; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Tzung-Hai
TH
Yen
Malcolm R
MR
Alison
Robert A
RA
Goodlad
William R
WR
Otto
Rosemary
R
Jeffery
H Terence
HT
Cook
Nicholas A
NA
Wright
Richard
R
Poulsom
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D007673:Kidney Cortex Necrosis / Q000139:chemically induced* / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D008627:Mercuric Chloride / Q000009:adverse effects*; D051379:Mice; D012038:Regeneration / Q000502:physiology*
D008627:Mercuric Chloride; D004815:Epidermal Growth Factor
acute tubular necrosis; bone marrow-derived cells; epidermal growth factor; mercuric chloride; pegfilgrastim; tubular regeneration