angiotensinogen and Uremia

Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal renin-angiotensin-aldosterone system (RAAS) and renal tubular epithelial-to-mesenchymal transition (EMT) in kidney fibrosis induced by (indoxyl sulfate) IS and (p-cresol sulfate) PCS.. Mouse proximal renal tubular cells (PKSV-PRs) treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks.. IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1) receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-β1 (TGF-β1) expression and activated the TGF-β pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and α-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-β1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo.. Activating the renal RAAS/TGF-β pathway has an important pathological role in chronic kidney injury caused by IS and PCS. IS and PCS may increase Snail expression and induce EMT-like transition.

Topics: Angiotensinogen; Animals; Cresols; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression Regulation; Indican; Kidney; Kidney Failure, Chronic; Kidney Tubules; Losartan; Male; Mice; Models, Biological; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Snail Family Transcription Factors; Sulfuric Acid Esters; Transcription Factors; Transforming Growth Factor beta1; Uremia

We studied the angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) gene polymorphisms for association with susceptibility to primary vesicoureteral reflux (VUR) and disease progression in 74 Taiwanese children, including 16 with end-stage renal disease (ESRD), and 117 normal controls. Polymerase chain reaction-amplified products containing the ACE gene T-5491C, A-5466C, T-3892C, A-3692C, A-240T, Alu I/D, the AGT gene C-532T, G-217A, G-152A, A-20C, A-6G, T174M, T235M, and the AT1R gene A-1138T, T-810A, T-713G, C-521T, AG-214CC, A-153G, A1166C polymorphisms were analyzed by restriction enzyme digestion, gel electrophoresis, or single-strand conformation polymorphism analysis. All the polymorphisms examined were in Hardy-Weinberg equilibrium. The strong non-random association within the ACE, AGT, and AT1R genes suggests low levels of intragenic recombination. None of these polymorphisms showed association with VUR susceptibility. However, the allele frequency distribution of the six ACE polymorphisms among primary VUR patients with or without ESRD was statistically different. The linked ACE T-A-T-A-A-I allele was observed significantly more frequently in VUR children with ESRD (P<0.001). A significant increase of left ventricular mass index was also found in the linked ACE T-A-T-A-A-I allele group compared with the non-ACE T-A-T-A-A-I allele group of patients aged 18 years with renal progression. The AGT A-6G genotype frequencies were significantly different when the analysis was stratified by genotype of the ACE polymorphisms. The data showed that ACE gene polymorphisms were associated with progressive renal deterioration in Taiwanese children with VUR and might act synergistically with the -6 G allele of the AGT gene.

Topics: Adolescent; Adult; Angiotensinogen; Child; Disease Progression; DNA Primers; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Linkage Disequilibrium; Male; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Taiwan; Uremia; Vesico-Ureteral Reflux

To examine and characterize the vascular renin--angiotensin system in low-renin models of renal hypertension with and without the presence of overt renal insufficiency, we studied the formation and metabolism of angiotensin in isolated perfused rat hindquarter preparations. Rats with 5/6 nephrectomy (5/6NX) and rats with one-kidney, one clip (1K1C) hypertension were compared to sham operated (sham) animals. Angiotensin peptides in plasma or perfusate were characterized by high-performance liquid chromatography and radioimmunoassay (RIA). Plasma angiotensin II was lower, and blood pressure was higher in both experimental groups, compared to sham animals. Plasma angiotensinogen, measured by both direct and indirect RIA, was increased in both experimental groups. The spontaneous release of angiotensin I and angiotensin II from perfused hindquarters did not differ between the groups. Angiotensin I conversion was not different in 5/6NX or 1K1C groups compared with controls. Furthermore, angiotensin conversion was completely inhibited by captopril (1 mumol/l) in all groups. Renin-induced angiotensin release was significantly increased in 5/6NX as compared with sham rats, whereas there was no difference in renin-induced angiotensin release between 1K1C and sham animals. Angiotensin II degradation was significantly attenuated in 5/6NX rats when compared with sham rats (27.6% versus 53.9%, respectively, P less than 0.05) but was unaltered in 1K1C rats. Thus, in chronic uremic hypertension, renin-induced angiotensin formation was increased in the face of decreased angiotensin II degradation. These data suggest that vascular angiotensin may contribute to the elevated blood pressure observed in chronic renal failure. In 1K1C rats, vascular angiotensin formation and metabolism was unchanged despite suppressed plasma angiotensin II.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Vessels; Chromatography, High Pressure Liquid; Hindlimb; Hypertension, Renal; Hypertension, Renovascular; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Uremia

The enzymatic activity of renin is increased in plasma of patients with renal failure, possibly because of the deficiency of a renin inhibitor. Our study was undertaken to identify renin inhibitors and to compare their activities in plasma of 10 normal humans and 10 patients with renal failure. In vitro, both human renal renin and purified mouse submaxillary renin were inhibited by intact plasma and by a high molecular weight (greater than 65,000 daltons) and a lower molecular weight (55,000 daltons) plasma fraction (HMF and LMF, respectively) obtained by Sephadex chromatography. Most plasma proteins were recovered in HMF, and LMF also contained a small amount of protein; however, renin inhibition by HMF and LMF was not dependent on the presence of intact protein. HMF extracted from normal and uremic plasma inhibited renin to a comparable extent. However, LMF from uremic plasma inhibited renin to a lesser extent (p less than 0.01) than LMF from normal plasma. HMF-free plasma of normal subjects contained a specific renin-inhibiting neutral lipid component that was absent in uremic plasma. Thus, circulating renin inhibitors may contribute to the overall activity of the renin-angiotensin system, and increased enzymatic activity of renin in plasma of patients with renal failure may be related to the deficiency of a normally occurring neutral lipid renin inhibitor.

Topics: Adult; Angiotensinogen; Animals; Blood Proteins; Female; Humans; In Vitro Techniques; Kidney; Lipids; Male; Mice; Middle Aged; Molecular Weight; Renin; Submandibular Gland; Uremia

Plasma renin reactivity (PRR) is the rate of angiotensin I production after addition of renin to plasma, minus endogenous renin activity. PRR is increased in plasma of patients with renal failure compared with that of normal subjects. The present study was carried out to determine if increased PRR in uraemic plasma is related to differences of endogenous active or inactive renin, endogenous renin substrate, or pH of the incubation in vitro. PRR in plasma of ten uraemic patients was greater (P less than 0.02) than that in plasma of ten normal subjects in incubations carried out at pH 7.4 and 5.7. Increased PRR was not accounted for by differences of endogenous active and inactive renin activity. After addition of renin, renin concentration (measured by direct radioimmunoassay) did not differ in normal and uraemic plasma. Renin substrate concentration, measured both indirectly and by direct radioimmunoassay, also did not differ in normal and uraemic plasma. Increased PRR in uraemic plasma is not related to alterations of renin or renin substrate concentrations. These observations are consistent with our earlier hypothesis that there is a deficiency of a renin inhibitor in uraemic plasma.

Topics: Angiotensinogen; Humans; Male; Renin; Renin-Angiotensin System; Uremia

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Cushing Syndrome; Diuretics; Electrophoresis, Polyacrylamide Gel; Female; Humans; Hypertension; Isoelectric Focusing; Kinetics; Liver Cirrhosis; Molecular Weight; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Regression Analysis; Uremia

The objective of this investigation was to determine whether heterogeneity of plasma renin substrate could be observed in states of steroid excess and various forms of hypertensive disease. In states of stimulated renin substrate production by estrogens or glucocorticoids, multiple forms of renin substrate were apparent when stimulation was excessive. Stimulation of substrate production caused by uremia associated with hypertension showed similar results. None, or only trace quantities of the additional forms of renin substrate were evident in subjects with normal or suppressed levels of plasma renin substrate. The additional forms of renin substrate could be distinguished from the normal form on the basis of cross-reactivity with a specific antiserum to the normal form, electrophoretic mobility, and kinetic rate constants. Differences in rate constants of the various forms of plasma renin substrate may account for the altered rate of the renin reaction associated with several states of hypertension. In plasma of patients with renovascular hypertension, significant quantities of a protein which cross-reacted with the antiserum but could not generate angiotensin I were observed.

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Cushing Syndrome; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Pregnancy; Uremia

After addition of exogenous human renin, the in vitro rate of angiotensin I generation is faster in plasma of patients with chronic renal insufficiency and, to a lesser extent, in plasma of patients with essential hypertension than in plasma from normotensive control subjects. The increased reactivity of renin in hypertensive and uremic plasma is not related to differences of endogenous renin activity, angiotensinase activity, renin substrate concentration, or substrate reactivity. Addition of normal, hypertensive, and uremic plasma to a human renin-sheep renin substrate system inhibited the rate of angiotensin generation, although significantly less inhibition was observed with uremic plasma. The reactivity of renin increased in normal plasma but not in uremic plasma after treatment with 95% acetone. After acetone extraction renin reactivity in normal and plasma inhibited the rate of angiotensin generation in a renin-renin substrate system. Less inhibition occurred with the acetone extract from a pool of uremic plasma. These results provide evidence for the existence of a naturally occurring acetone soluble renin inhibiting factor in normal and uremic plasma. The increased reactivity of renin in uremic plasma may be related to a deficiency of this factor.

Topics: Acetone; Angiotensin II; Angiotensinogen; Humans; Hypertension; In Vitro Techniques; Kinetics; Radioimmunoassay; Renin; Solubility; Time Factors; Uremia