title: Renal failure affects the enzymatic activities of the three first steps in hepatic heme biosynthesis in the acute intermittent porphyria mouse.
abstract: Chronic kidney disease is a long-term complication in acute intermittent porphyria (AIP). The pathophysiological significance of hepatic overproduction of the porphyrin precursors aminolevulinate acid (ALA) and porphobilinogen (PBG) in chronic kidney disease is unclear. We have investigated the effect of repetitive acute attacks on renal function and the effect of total or five-sixth nephrectomy causing renal insufficiency on hepatic heme synthesis in the porphobilinogen deaminase (PBGD)-deficient (AIP) mouse. Phenobarbital challenge in the AIP-mice increased urinary porphyrin precursor excretion. Successive attacks throughout 14 weeks led to minor renal lesions with no impact on renal function. In the liver of wild type and AIP mice, 5/6 nephrectomy enhanced transcription of the first and rate-limiting ALA synthase. As a consequence, urinary PBG excretion increased in AIP mice. The PBG/ALA ratio increased from 1 in sham operated AIP animals to over 5 (males) and over 13 (females) in the 5/6 nephrectomized mice. Total nephrectomy caused a rapid decrease in PBGD activity without changes in enzyme protein level in the AIP mice but not in the wild type animals. In conclusion, high concentration of porphyrin precursors had little impact on renal function. However, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure.
authors.affiliation: Gene Therapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Unzu
authors.forename: Ana
authors.initials: A
authors.lastname: Sampedro
authors.forename: Eliane
authors.initials: E
authors.lastname: Sardh
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleón
authors.forename: Rafael
authors.initials: R
authors.lastname: Enríquez de Salamanca
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.forename: Pauline
authors.initials: P
authors.lastname: Harper
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D000622:Aminolevulinic Acid / Q000652:urine; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D006418:Heme / Q000096:biosynthesis*; D011163:Hydroxymethylbilane Synthase / Q000378:metabolism*; D007677:Kidney Function Tests; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy / Q000009:adverse effects; D017118:Porphyria, Acute Intermittent / Q000150:complications* / Q000201:enzymology*; D011165:Porphyrinogens / Q000652:urine; D011166:Porphyrins / Q000652:urine; D051437:Renal Insufficiency / Q000201:enzymology* / Q000209:etiology*; D012737:Sex Factors
chemical_list: D011165:Porphyrinogens; D011166:Porphyrins; D006418:Heme; D000622:Aminolevulinic Acid; D011163:Hydroxymethylbilane Synthase