Chronic renal
fibrosis is the final common pathway of
end stage renal disease caused by glomerular or tubular pathologies. Genetic background has a strong influence on the progression of chronic renal
fibrosis. We recently found that Rowett black hooded rats were resistant to renal
fibrosis. We aimed to investigate the role of sustained
inflammation and oxidative/nitrative stress in renal
fibrosis progression using this new model. Our previous data suggested the involvement of podocytes, thus we investigated renal
fibrosis initiated by
doxorubicin-induced (5 mg/kg) podocyte damage.
Doxorubicin induced progressive glomerular
sclerosis followed by increasing
proteinuria and reduced bodyweight gain in
fibrosis-sensitive, Charles Dawley rats during an 8-week long observation period. In comparison, the
fibrosis-resistant, Rowett black hooded rats had longer survival, milder
proteinuria and reduced tubular damage as assessed by
neutrophil gelatinase-associated lipocalin (NGAL) excretion, reduced loss of the slit diaphragm
protein,
nephrin, less glomerulosclerosis, tubulointerstitial
fibrosis and matrix deposition assessed by
periodic acid-Schiff, Picro-Sirius-red staining and
fibronectin immunostaining. Less
fibrosis was associated with reduced profibrotic
transforming growth factor-beta, (TGF-β1)
connective tissue growth factor (CTGF), and
collagen type I alpha 1 (COL-1a1)
mRNA levels. Milder
inflammation demonstrated by histology was confirmed by less
monocyte chemotactic protein 1 (MCP-1)
mRNA. As a consequence of less
inflammation, less oxidative and nitrative stress was obvious by less
neutrophil cytosolic factor 1 (p47phox) and
NADPH oxidase-2 (p91phox)
mRNA. Reduced oxidative
enzyme expression was accompanied by less lipid peroxidation as demonstrated by
4-hydroxynonenal (HNE) and less
protein nitrosylation demonstrated by
nitrotyrosine (NT) immunohistochemistry and quantified by Western blot. Our results demonstrate that mediators of
fibrosis,
inflammation and oxidative/nitrative stress were suppressed in
doxorubicin nephropathy in
fibrosis-resistant Rowett black hooded rats underlying the importance of these pathomechanisms in the progression of renal
fibrosis initiated by glomerular podocyte damage.