Albuminuria in patients with type 1 diabetes is directly linked to changes in the lysosome-mediated degradation of albumin during renal passage.
Previous studies by our group have shown that albumin is metabolized in rodents during renal passage and excreted in the urine as a mixture of intact protein and albumin-derived fragments. The aim of this study was to examine whether albumin is metabolized during renal passage in nondiabetic volunteers and in type 1 diabetic patients with varying levels of albuminuria. Nine nondiabetic normoalbuminuric volunteers and 11 type 1 diabetic patients with albumin excretion rates varying from normoalbuminuria to macroalbuminuria were studied. Each subject received an intravenous injection of tritium-labeled albumin ([3H]-albumin). Urine was collected at 4 h and 24 h after injection and analyzed by size exclusion chromatography. The amount of intact and fragmented albumin was quantified, and each fraction was analyzed by radioimmunoassay (RIA) for albumin. [3H]-albumin in nondiabetic volunteers was metabolized during renal passage to small peptide fragments not detectable by conventional RIA (only 0.05-3.8% of the total urinary radioactivity was associated with intact albumin). The process responsible for albumin fragmentation was similar in diabetic patients with normoalbuminuria (intact albumin represented 0.01-4.0% of total urinary radioactivity). However, there was a reduction in the fragmentation ratio (fragmented:intact) in diabetic patients with micro- or macroalbuminuria (intact albumin represented 2.7-55.5%, P = 0.048). This change in the fragmentation ratio was directly related to the degree of albuminuria. These results have important implications for understanding the mechanisms underlying albuminuria in nondiabetic volunteers and type 1 diabetic patients. In nondiabetic volunteers, the renal processing of albumin involves a relatively rapid and comprehensive degradation of albumin to small fragments (range 1-15 kDa). The degradation process is inhibited in diabetic nephropathy in proportion to the level of albuminuria detected by RIA.
Osicka
T M
TM
Department of Medicine, Austin & Repatriation Medical Center, University of Melbourne, Heidelberg, Victoria, Australia.
Houlihan
C A
CA
Chan
J G
JG
Jerums
G
G
Comper
W D
WD
D000328:Adult; D000368:Aged; D000419:Albuminuria; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology* / Q000652:urine; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000652:urine; D005260:Female; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012709:Serum Albumin / Q000378:metabolism*; D014316:Tritium
D012709:Serum Albumin; D014316:Tritium