angiotensinogen and Glomerulosclerosis--Focal-Segmental

Topics: Angiotensinogen; Antigens, CD; Child; DNA-Binding Proteins; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; I-kappa B Proteins; Kidney Transplantation; NF-kappa B; NF-KappaB Inhibitor alpha; Secondary Prevention; Steroids

This study aimed to investigate the effect of combination of high-salt intake and hypertension on renal functional and histological damage, associated with renal (pro)renin receptor [(P)RR] and AT1 receptor in rats.. Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received regular rat chow (normal-salt diet 0.9%) or high-salt rat chow (high-salt diet 8.9%) for 6 weeks from 6 to 12 weeks of age. Systolic blood pressure, serum creatinine and blood urea nitrogen (BUN) were measured. Histological analysis of the kidney was performed. Western blot analysis was performed on the expressions of (P)RR, angiotensinogen and AT1 receptor in the kidney.. High-salt intake significantly increased systolic blood pressure in WKYs and especially in SHRs. High-salt intake significantly increased serum creatinine and BUN, and accelerated renal tubulointerstitial fibrosis and glomerular sclerosis in SHRs. High-salt intake significantly enhanced the renal tissue expressions of (P)RR, angiotensinogen and AT1 receptor in SHRs.. High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (P)RR and AT1 receptors in SHRs.

Topics: Angiotensinogen; Animals; Blood Pressure; Blood Urea Nitrogen; Body Weight; Creatinine; Fibrosis; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prorenin Receptor; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Signal Transduction; Sodium Chloride, Dietary; Systole

Urinary protein (UP) is widely used as a clinical marker for podocyte injury; however, not all proteinuric nephropathies fit this model. We previously described the elevation of urinary angiotensinogen (AGT) accompanied by AGT expression by injured podocytes in a nitric oxide inhibition rat model (Eriguchi M, Tsuruya K, Haruyama N, Yamada S, Tanaka S, Suehiro T, Noguchi H, Masutani K, Torisu K, Kitazono T. Kidney Int 87: 116-127, 2015). In this report, we performed the human and animal studies to examine the significance and origin of urinary AGT. In the human study, focal segmental glomerulosclerosis (FSGS) patients presented with higher levels of urinary AGT, corrected by UP, than minimal-change disease (MCD) patients. Furthermore, AGT was evident in podocin-negative glomerular segmental lesions. We also tested two different nephrotic models induced by puromycin aminonucleoside in Wistar rats. The urinary AGT/UP ratio and AGT protein and mRNA expression in sieved glomeruli from FSGS rats were significantly higher than in MCD rats. The presence of AGT at injured podocytes in FSGS rats was detected by immunohistochemistry and immunoelectron microscopy. Finally, we observed the renal tissue and urinary metabolism of exogenous injected human recombinant AGT (which is not cleaved by rodent renin) in FSGS and control rats. Significant amounts of human AGT were detected in the urine of FSGS rats, but not of control rats. Immunostaining for rat and human AGT identified that only rat AGT was detected in injured podocytes, and filtered human AGT was seen in superficial proximal tubules, but not in injured podocytes, suggesting AGT generation by injured podocytes. In conclusion, the urinary AGT/UP ratio represents a novel specific marker of podocyte injury.

Topics: Adult; Aged; Angiotensinogen; Animals; Antibiotics, Antineoplastic; Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Proximal; Male; Middle Aged; Nephrosis, Lipoid; Podocytes; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Wistar

Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function. The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice.. Mice heterozygous for an AM-null mutation (AM+/-) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-beta, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AM+/- mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AM+/- mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AM+/- myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II-induced ERK activation via a protein kinase A-dependent pathway.. Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase C- and protein kinase A-dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.

Topics: Adrenomedullin; Angiotensin II; Angiotensinogen; Animals; Aorta, Abdominal; Cardiomegaly; Collagen Type I; Constriction; Enzyme Activation; Enzyme Inhibitors; Fibroblasts; Fibrosis; Gene Expression Regulation; Genes, fos; Genes, Lethal; Glomerulosclerosis, Focal Segmental; Heterozygote; Male; MAP Kinase Signaling System; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Natriuretic Peptide, Brain; Peptides; Peptidyl-Dipeptidase A; Protein Kinase C; Proto-Oncogene Proteins c-fos; Transforming Growth Factor beta; Ventricular Remodeling

The renin-angiotensin system (RAS) is implicated in the development of hypertensive glomerulosclerosis. However, no experimental evidence exists that clearly demonstrates activation of glomerular RAS in hypertensive nephropathy. We used stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether RAS components are increased in glomeruli of SHRSP and whether this increase leads to an increase in mRNA levels for transforming growth factor-beta1 (TGF-beta1).. We examined the sequential changes of urinary albumin excretion (UAE), morphology, and glomerular mRNA expression for TGF-beta1 and fibronectin (FN) in relation to glomerular mRNA expression for angiotensinogen (ATN), angiotensin converting enzyme (ACE), angiotensin II type 1a (AT1a), and type 1b (AT1b) receptors, and intervention with angiotensin II type 1 receptor antagonist candesartan and equihypotensive hydralazine.. In SHRSP, UAE was normal at 9 weeks of age, but became higher, beginning at 12 weeks of age, than that in the age-matched Wistar-Kyoto (WKY) rats, while SHRSP showed no glomerulosclerosis until 14 weeks of age; it was marked at 24 weeks. Plasma renin activity and plasma angiotensin II level was equivalent in the 9- and 12-week-old SHRSP and the WKY rats; both parameters, however, were elevated in 24-week-old SHRSP as compared with age-matched control. RNase protection assays showed that glomerular levels of ATN, ACE, and AT1a and AT1b receptors mRNA were significantly increased in 9-, 12-, and 14-week-old, but not in 24-week-old SHRSP, compared with age-matched WKY rats. Northern blot analysis showed that glomerular levels of TGF-beta1 and FN mRNA were higher in SHRSP than in WKY rats at all time points. Candesartan reduced UAE to control levels, whereas hydralazine reduced UAE but not to control levels. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis. While candesartan reduced mRNA levels for RAS components, TGF-beta1, and FN to control levels, hydralazine was not effective in this respect. Conclusion Results suggest that increases in glomerular RAS components that occur independently of circulating RAS alter glomerular permselectivity and increase the glomerular expression of TGF-beta1 and FN in young SHRSP. Findings in old SHRSP suggest that altered glomerular permselectivity and an increased glomerular expression of TGF-beta1 and FN may be associated with the activation of systemic RAS.

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blotting, Northern; Fibronectins; Gene Expression; Glomerulosclerosis, Focal Segmental; Hydralazine; Hypertension, Renal; Kidney Glomerulus; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Ribonucleases; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

In an attempt to identify potential markers of steroid-resistance in focal segmental glomerulosclerosis (FSGS) we evaluated intra-graft gene expression of IkappaBalpha, nuclear factor-kappaB (NF-kappaB), and angiotensinogen in 60 biopsies from 27 pediatric renal transplant recipients. Intra-graft NF-kappaB expression was significantly elevated in recurrent FSGS (R-FSGS) (218.3 + 55.6 ag/fg versus NON-FSGS 121.1 + 19.9, P=0.04) but not in acute rejection. NF-kappaB:IkappaBalpha ratios were higher in cadaveric donor versus living related donor recipients (15.7 + 2.8 vs. 8.8 + 1.3, respectively, P=0.015), and in African-American versus Caucasian recipients (15.6 + 2.9 vs. 9.1 + 1.3, respectively, P=0.03). Intra-graft angiotensinogen gene expression was significantly elevated in R-FSGS (30.5 + 8.8 ag/fg R-FSGS vs. 16.0 + 4.7 NON-FSGS, P=0.009). We conclude that increased NF-kappaB and angiotensinogen gene expression are associated with R-FSGS. Increased NF-kappaB:IkappaBalpha ratios are associated with cadaveric donor recipients and African-American race.

Topics: Adolescent; Angiotensinogen; Child; Child, Preschool; Gene Expression; Glomerulosclerosis, Focal Segmental; Humans; Kidney Transplantation; NF-kappa B; Postoperative Complications; Recurrence

Tsukuba hypertensive mice (THMs) are transgenic mice carrying human renin and angiotensinogen genes. The aim of this study was to evaluate the role of the renin-angiotensin system (RAS) in cardiac hypertrophy and renal disorders in THMs. After a 2-wk control period, 10-wk-old THMs were treated with lisinopril (ACEI group) or hydralazine (hydralazine group) or left untreated (control group) for 8 wk. C57BL/6 mice of similar age (wild group) were used as normal controls. Systolic blood pressure and urinary albumin excretion were measured once a week. All mice were sacrificed at 20 wk of age, and heart to body weight ratio, cardiac myocyte diameter, renal glomerular sclerosis index, and glomerular size were measured. Fibronectin expression was also evaluated. At 20 wk of age, systolic blood pressure and urinary albumin excretion in the control group were significantly higher than those in the wild group and significantly lower than those in the ACEI and hydralazine groups. Heart to body weight ratio and cardiac myocyte diameter were significantly higher in the hydralazine and control groups than in the other groups. Renal glomerular sclerosis index and glomerular size were also significantly higher in the control group than in the other groups, and there were significant differences between the ACEI and hydralazine groups in these variables. Fibronectin expression was marked in the control and hydralazine groups. These findings suggest that the RAS plays an important role in cardiac hypertrophy in THMs, but that both the RAS and elevation of blood pressure contribute to the pathogenesis of renal glomerular sclerosis.

Topics: Albuminuria; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Drinking; Fibronectins; Gene Expression; Glomerulosclerosis, Focal Segmental; Heart Rate; Humans; Hydralazine; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Renin; Renin-Angiotensin System; Vasodilator Agents

Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findings, it was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hypertrophy and renal glomerular sclerosis by inhibiting RAS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Cardiomegaly; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Kidney; Lisinopril; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Renin; Renin-Angiotensin System

The clinical course of primary focal segmental glomerulosclerosis (FSGS) in children is variable, with some patients having a much more rapidly progressing course than others. The purpose of our study was to compare the frequency of three polymorphisms of the renin-angiotensin system (RAS) in children with FSGS with that in healthy controls of matching ethnic groups, and to determine whether the clinical outcome of FSGS was associated with different RAS genotypes.. Three RAS genotypes were examined in 47 Jewish and Arab children with biopsy-proven primary FSGS and in a large control group: the ACE insertion/deletion polymorphism in intron 16, the M235T mutation in the angiotensinogen gene, and the A1166C in the angiotensin II type 1 receptor gene (AT1R).. Arab patients showed a greater tendency towards progressive renal disease than their Jewish counterparts (12 of 21 vs. 9 of 26, P = 0.05) and were less likely to achieve remission (3 of 21 vs. 11 of 26, P < 0.04), despite similar clinical presentation, medical management and follow-up. The RAS allele prevalence was similar among patients and controls of matching ethnic backgrounds, and no difference in allele frequency was found between Arabs and Jews. Homozygotes for the ACE insertion genotype (II) were significantly less likely to have progressive renal disease than patients with the other genotypes (ID and DD; 0 of 6 vs. 21 of 41; P < 0.022). The other RAS polymorphisms were not associated with variations in the clinical course of childhood FSGS.. Homozygosity for the ACE insertion allele may have a protective effect in children with FSGS and can serve as a positive prognostic indicator at diagnosis. The D allele may exert a detrimental dominant effect on outcome. Neither the ACE gene polymorphism nor the other RAS polymorphisms studied are associated with disease prevalence. The AT1R and angiotensinogen gene polymorphisms are not associated with progression of renal disease in FSGS. Ethnic differences in the clinical course of the disease are not linked to these polymorphisms.

Topics: Adolescent; Alleles; Angiotensinogen; Child; Child, Preschool; Disease Progression; DNA Transposable Elements; Female; Gene Deletion; Glomerulosclerosis, Focal Segmental; Humans; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prevalence; Prognosis; Renin-Angiotensin System

Locally activated renin angiotensin system plays an important role in the progression of the glomerular diseases. In order to understand the local effect of overexpressed angiotensin II in the glomerulus in situ, we introduced human genes for renin and angiotensinogen into the rat kidney by hemagglutinating virus of Japan-liposome procedure. Three days after transfection human renin was detected in the glomeruli by immunohistochemistry. Seven days after transfection, extracellular matrix was expanded in the glomeruli and alpha-smooth muscle actin was expressed in the mesangial cells. These results suggest that locally activated renin angiotensin system induces glomerular sclerosis and a phenotypic change in mesangial cells.

Topics: Actins; Angiotensinogen; Animals; Antibodies, Monoclonal; Cattle; Chickens; Collagen; Gene Expression; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Phenotype; Plasmids; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Transfection

An association between the activity of the renin-angiotensin system and the development of spontaneous focal glomerular sclerosis (FGS) in rats has been observed: the onset is preceded by a decrease in plasma renin activity (PRA). This observation was facilitated by the use of Fawn-hooded rats, which develop spontaneous FGS at an early age. Male Fawn-hooded rats develop severe FGS as early as 3 months of age. Male Wistar rats do not develop similar lesions until after 1 year of age. Correspondingly the PRA drops much sooner in Fawn-hooded than in Wistar rats. The low PRA appears to be due to low plasma renin rather than a limitation of the renin substrate, angiotensinogen, which appears to be present in the Fawn-hooded plasma in nonlimiting quantities. In the FH male rats renin content of the kidney drops only after severe glomerular pathology is evident, implying that the low PRA may be due to a decrease in renin secretion by the chromaffin cells of the juxtaglomerular apparatus.

Topics: Aging; Angiotensinogen; Animals; Female; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Juxtaglomerular Apparatus; Male; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System