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Lysosomal enzymuria is a feature of hereditary Fanconi syndrome and is related to elevated CI-mannose-6-P-receptor excretion.
- Source :
-
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association [Nephrol Dial Transplant] 2008 Sep; Vol. 23 (9), pp. 2795-803. Date of Electronic Publication: 2008 Jan 03. - Publication Year :
- 2008
-
Abstract
- Background: Lysosomal enzymuria is usually considered to be a non-specific marker of renal injury, but little is known about lysosomal enzyme excretion in renal proximal tubular cell disorders such as the renal Fanconi syndrome (FS). We examined excretion of two lysosomal enzymes and the cation-independent mannose-6-phosphate receptor (CI-MPR) in patients with inherited FS.<br />Methods: The lysosomal enzyme cathepsin D was measured by ELISA and isolated by pepstatin-agarose affinity chromatography; N-acetyl-beta-d-glucosaminidase (NAG) was assayed colorimetrically, as was the cytosolic enzyme lactate dehydrogenase (LDH). Cathepsin D, procathepsin D and CI-MPR were also detected by western blotting. No patient had a serum creatinine concentration >170 micromol/L. Soluble CI-MPR, isolated from fetal calf serum and bound to agarose, was used to probe cathepsin D for mannose-6-phosphate (M6P).<br />Results: Increased excretion of cathepsin D (mean = 44-fold) and NAG (mean = 12-fold) was found in FS patients: Dent's disease (n = 5), cystinosis (n = 4), Lowe syndrome (n = 3) and 'autosomal dominant idiopathic FS' (ADIF) (n = 2). Increased cathepsin D excretion was confirmed by western blotting; excretion of procathepsin D and LDH was not increased. When compared with control subjects, CI-MPR excretion was also increased in FS (n = 6). Thus, significantly increased excretion of lysosomal enzymes and CI-MPR was found in all cases of FS examined. Cathepsin D binding to CI-MPR-agarose was inhibited by M6P.<br />Conclusions: We conclude that underlying gene defects in FS may disrupt normal membrane trafficking of CI-MPR, leading to mistrafficking of lysosomal enzymes via a default pathway from the Golgi to the apical surface of proximal tubule cells rather than to lysosomes. Lysosomal enzymes are then secreted into the tubular fluid and excreted in the urine. This contrasts with the widely held view that cell necrosis is the cause of lysosomal enzymuria in renal disease. Moreover, cathepsin D in FS urine is M6P-tagged.
- Subjects :
- Acetylglucosaminidase metabolism
Acetylglucosaminidase urine
Adult
Blotting, Western
Cathepsin D urine
Child
Chromatography, Affinity
Cystinosis metabolism
Fanconi Syndrome genetics
Humans
L-Lactate Dehydrogenase urine
Protein Transport
Proteinuria physiopathology
Receptor, IGF Type 2
Young Adult
Cathepsin D metabolism
Fanconi Syndrome physiopathology
Kidney Tubules, Proximal physiopathology
Lysosomes enzymology
Receptors, Cytoplasmic and Nuclear metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2385
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
- Publication Type :
- Academic Journal
- Accession number :
- 18174267
- Full Text :
- https://doi.org/10.1093/ndt/gfm898