Determination of renal porphyrin handling in rats suffering from different kinds of chronic renal failure (CRF): uranyl nitrate (UN) induced fibrosis or 5/6-nephrectomy (5/6NX).
The renal handling of porphyrins is reported to be a sensitive marker for chronic renal failure (CRF) for two reasons: heme is synthesised in proximal tubules and porphyrins are reabsorbed in the renal proximal tubule by apical peptide transporter PEPT 2. Two different models of CRF in female Wistar rats have been used for investigation of renal porphyrin handling: (1) single administration of uranyl nitrate (UN; 0.5 mg/100 g b.wt.) and (2) 5/6 nephrectomy (5/6NX). Renal clearance experiments were performed at weeks 2 and 10 after the onset of CRF. The concentrations of porphyrin intermediates (uroporphyrin I and III, coproporphyrin I and II, heptaporphyrin, and pentaporphyrin) were measured by HPLC with fluorescence detection. Both after UN and 5/6NX a significant reduction of body weight occurred. The kidney weight was enhanced 2 weeks after UN compared to controls (+31%). After 5/6NX, the weight of the remnant kidney was 44% (2nd week) and 140% (10th week) higher compared to one control kidney. Urine volumes and GFR were significantly reduced at week 2 and 10 after 5/6NX, but at week 10 after UN values were comparable to controls. Two weeks after UN and 5/6NX the concentrations of heptaporphyrin was moderately decreased in renal tissue whereas after 10 weeks the concentrations of most porphyrins were increased in the kidney. The plasma levels of free porphyrins were only slightly enhanced (week 2). The renal excretion of porphyrins was initially slightly reduced in both models, whereas it increases 10 weeks after UN, but it remained reduced 10 weeks after 5/6NX. UN induces tubulointerstitial fibrosis including atrophic glomeruli, whereas 5/6NX was characterized by distinct proteinuria, dilated tubules containing hyaline casts. A modulation of porphyrin metabolism in the kidney seems first of all to be responsible for UN effect on renal porphyrin handling. Summing up the 5/6NX results, both reduction in intact renal tissue mass and a modification of enzymes involved in heme biosynthesis by uraemic toxins are responsible for accumulation of porphyrins in renal tissue. After 5/6NX reduced excretion of porphyrins into urine and enhanced porphyrin concentrations in the kidney indicate more a damage of renal porphyrin biosynthesis than changes in their reabsorption.
Fleck
Christian
C
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Germany. Christian.Fleck@mti.uni-jena.de
Scholle
Thorsten
T
Schwertfeger
Markus
M
Appenroth
Dorothea
D
Stein
Gonter
G
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011166:Porphyrins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014502:Uranyl Nitrate / Q000633:toxicity
D011166:Porphyrins; D014502:Uranyl Nitrate