ABSTRACT
Chronic renal disease is characterized by the accumulation of extracellular matrix proteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis has been reported to play an important role in the progression of chronic renal diseases. Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine playing a major contribution to fibrotic kidney disease. Endoglin is a membrane glycoprotein of the TGF-beta1 receptor system. The aim of this work was to determine the time-course expression of renal type I and IV collagens, endoglin and TGF-beta1 in a rat model of induced tubulointerstitial fibrosis at 1, 3, 10 and 17 days after unilateral ureteral obstruction (UUO). In 17 days-ligated (L)-renal samples, a marked interstitial fibrosis was detected by Masson's trichromic and Sirius red staining, accompanied by an increase in type I collagen expression as shown by immunohistochemical analysis. Northern blot studies revealed a progressive increase in collagen alpha2(I), TGF-beta1 and endoglin mRNA expression in L kidneys when compared with the corresponding non-ligated (NL) kidneys from the animals subjected to left UUO. Seventeen days after UUO, significant increases in collagen alpha2(I), collagen alpha1(IV), TGF-beta1 and endoglin mRNA levels were detected in L kidneys vs NL kidneys. Significantly higher levels of the protein endoglin were found in L kidneys than in NL kidneys 10 and 17 days following obstruction. A marked increase expression for endoglin and TGF-beta1 was localized in renal interstitium by immunohistochemical studies 17 days after obstruction. In conclusion, this work reports the upregulation of endoglin coincident to that of its ligand TGF-beta1 in the kidneys of rats with progressive tubulointerstitial fibrosis induced by UUO.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Kidney/metabolism , Transforming Growth Factor beta/metabolism , Ureteral Obstruction , Animals , Blotting, Northern , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type IV/genetics , Collagen Type IV/metabolism , Endoglin , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/genetics , Male , RNA, Messenger/genetics , Rats , Rats, Wistar , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1Subject(s)
Signal Transduction/physiology , Transforming Growth Factor beta/physiology , Animals , Antigens, CD , Chickens/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/physiology , Endoglin , Gene Expression Regulation , Humans , Macromolecular Substances , Mammals/metabolism , Phosphorylation , Promoter Regions, Genetic , Protein Isoforms/physiology , Protein Precursors/biosynthesis , Protein Processing, Post-Translational , Proteoglycans/drug effects , Receptors, Cell Surface , Receptors, Transforming Growth Factor beta/classification , Receptors, Transforming Growth Factor beta/drug effects , Receptors, Transforming Growth Factor beta/physiology , Species Specificity , Substrate Specificity , Transcription Factors/chemistry , Transcription Factors/physiology , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/classification , Transforming Growth Factor beta/pharmacology , Vascular Cell Adhesion Molecule-1/drug effects , Xenopus laevis/metabolismABSTRACT
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Subject(s)
Animals , Humans , Substrate Specificity , Species Specificity , Transcription Factors , Xenopus laevis , Signal Transduction , Vascular Cell Adhesion Molecule-1 , Phosphorylation , Protein Processing, Post-Translational , Promoter Regions, Genetic , Proteoglycans , Protein Precursors , Protein Isoforms , Chickens , Mammals , Gene Expression Regulation , Transforming Growth Factor beta , Receptors, Transforming Growth Factor beta , DNA-Binding Proteins , Macromolecular SubstancesABSTRACT
BACKGROUND: The central process in chronic renal failure is the progressive accumulation of extracellular matrix in the glomeruli and in the tubulo-interstitial space, resulting in renal fibrosis. Transforming growth factor-beta1 (TGF-beta1) up-regulation plays a major role in the genesis of renal fibrosis. Endoglin is a membrane glycoprotein that binds TGF-beta1 and TGF-beta3 with high affinity. An increased level of endoglin immunostaining has been demonstrated previously in biopsies from patients with chronic progressive renal disease. We have assessed the expression of endoglin in the rat 5/6th renal mass reduction (RMR) model. METHODS: One, 3 and 5 months after RMR, mean arterial pressure and renal function were measured, animals were sacrificed, renal fibrosis was evaluated quantitatively and the expression of endoglin was assessed by western blot, northern blot and immunohistochemistry. RESULTS: RMR induced a progressive increase in mean arterial pressure and urinary protein excretion. Renal corpuscular area, and mesangial and interstitial fibrosis increased with time after RMR. Immunohistochemical staining for endoglin demonstrated its expression mainly on the endothelial surface of major vessels. In kidneys 1 and 3 months after RMR, the expression of endoglin in renal corpuscles was limited to Bowman's parietal epithelium. In rats 5 months after RMR, the immunoexpression in glomerular endothelium was more marked. Northern blot analysis revealed that rats with RMR showed an increase in the expression of mRNA for endoglin, only at 5 months after RMR. Western blot analysis gave a different time course: a marked increase in the first month, a decrease in the 3rd month and a further increase in the 5th month after RMR. CONCLUSIONS: The present study demonstrates increased endoglin expression in rats with severe hypertension and renal damage. This increased endoglin expression coincides with the period of higher renal damage and renal dysfunction.
