Albuminuria in hypertension is linked to altered lysosomal activity and TGF-beta1 expression.
Increased intraglomerular pressure is considered a major factor for increased albumin excretion in hypertension. However, other factors should also be considered because recent studies in both humans and rats have demonstrated that proteins undergoing filtration and renal passage are extensively modified by renal cell lysosomal processing; >95% of albumin is degraded to peptides that are not detected by routine immunochemical assays. Changes in postglomerular lysosomal processing may therefore be responsible for the increased intact albumin excreted in hypertension-related kidney disease. We hypothesize that transforming growth factor-beta, which is known to decrease lysosomal activity, may be upregulated in hypertension and may play a role in increased intact albumin excretion. The aims of this study were to determine the effect that hypertension has on (1) renal cell lysosomal processing of albumin and dextran sulfate, (2) glomerular permeability, and (3) renal transforming growth factor-beta(1) expression. Spontaneously hypertensive rats and Wistar-Kyoto rats were used at 8, 16, and 24 weeks. We demonstrate that albuminuria in hypertension is linked to an inhibition of lysosomal processing as determined by (1) size exclusion chromatography analysis of urinary [(14)C]albumin structural integrity and (2) ion exchange analysis of urinary [(3)H]dextran sulfate. This inhibition gives rise to an increased proportion of radioimmunoassay detectable (intact) albumin and intact dextran sulfate independent of changes in glomerular capillary wall permeability as determined by the fractional clearance of [(3)H]Ficolls of various radii. These changes may be correlated with increased renal transforming growth factor-beta(1) expression.
Russo
Leileata M
LM
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Osicka
Tanya M
TM
Bonnet
Fabrice
F
Jerums
George
G
Comper
Wayne D
WD
D000419:Albuminuria / Q000652:urine*; D000818:Animals; D001794:Blood Pressure; D016326:Extracellular Matrix Proteins; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000652:urine*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013429:Sulfatases / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013429:Sulfatases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C508962:Tgfb1 protein, rat