Hypertension-mediated albuminuria is associated with reduced lysosomal activity in the kidney and the heart.
BACKGROUND
Recent studies suggest that expression of the transforming growth factor-beta (TGF-beta)-inducible gene-h3 (betaig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension.


METHODS
We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson's trichrome stain. Renal and cardiac TGF-beta(1) and betaig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity.


RESULTS
SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal betaig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-beta(1) and betaig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment.


CONCLUSIONS
These findings implicate for the first time betaig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension.
Hilliard
Lucinda M
LM
Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Melbourne, Victoria, Australia.
Russo
Leileata M
LM
Comper
Wayne D
WD
D000419:Albuminuria / Q000209:etiology / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D000099222:betaIG-H3 Protein
D000806:Angiotensin-Converting Enzyme Inhibitors; D002403:Cathepsins; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D017257:Ramipril; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C508962:Tgfb1 protein, rat