Renal processing of albumin in diabetes and hypertension in rats: possible role of TGF-beta1.

Recent studies show that albuminuria may be the result of changes in post-glomerular cellular uptake and processing of albumin. This study aims to determine whether this processing is disrupted in diabetes and/or hypertension. Diabetes (d) was induced using streptozotocin in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) and studied after 8, 16 and 24 weeks of disease. Intact albumin excretion was determined by radioimmunoassay. Total albumin was determined by [(14)C]albumin. Lysosomal activity was determined by dextran sulfate desulfation. Renal TGF-beta1 and transforming growth factor-beta1 inducible gene-h3 mRNA (betaig-h3) expression was determined by real time RT-PCR. SHR-c rats exhibited an increase in intact albuminuria without significant change in total albumin excretion (intact plus albumin-derived peptides). For WKY-d rats, intact albuminuria developed initially, followed by an increase in total albumin excretion primarily in the form of albumin peptides (peptiduria). SHR-d rats exhibited both increases in peptiduria and intact albuminuria. There was no increase in glomerular permeability at 24 weeks for polydisperse [(3)H]Ficoll in all groups. Increased renal TGF-beta1 and betaig-h3 expression was correlated with a decrease in dextran sulfate desulfation and increased intact albuminuria independent of peptiduria. Increased albumin excretion in hypertension and/or diabetes is manifested in different forms independent of glomerular permeability.

Russo LM ，Osicka TM ，Brammar GC ，Candido R ，Jerums G ，Comper WD ... -  《AMERICAN JOURNAL OF NEPHROLOGY》

The effect of ramipril on albumin excretion in diabetes and hypertension: the role of increased lysosomal activity and decreased transforming growth factor-beta expression.

Russo LM ，Brammar GC ，Jerums G ，Comper WD ，Osicka TM ... -  《JOURNAL OF HYPERTENSION》

Albuminuria in hypertension is linked to altered lysosomal activity and TGF-beta1 expression.

Russo LM ，Osicka TM ，Bonnet F ，Jerums G ，Comper WD ... -  《-》

Hypertension-mediated albuminuria is associated with reduced lysosomal activity in the kidney and the heart.

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. 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. 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. 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 LM ，Russo LM ，Comper WD 《-》

Additive effects of hypertension and diabetes on renal cortical expression of PKC-alpha and -epsilon and alpha-tubulin but not PKC-beta 1 and -beta 2.

Osicka TM ，Russo LM ，Qiu ML ，Brammar GC ，Thallas V ，Forbes JM ，Comper WD ，Jerums G ... -  《-》