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Jeffrey B. Kopp - One of the best experts on this subject based on the ideXlab platform.
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apol1 risk alleles are associated with more severe arteriosclerosis in renal resistance vessels with aging and hypertension
Kidney International Reports, 2016Co-Authors: Michael D Hughson, Susan A Mott, Victor G Puelles, John F Bertram, Cheryl A Winkler, Jeffrey B. KoppAbstract:Introduction The increased risk of end-stage kidney disease among hypertensive African Americans is partly related to APOL1 allele variants. The initial Glomerulosclerosis of hypertension-associated arterionephrosclerosis consists of focal global Glomerulosclerosis, but in biopsy studies, focal segmental Glomerulosclerosis is found with progression to end-stage kidney disease, particularly in African Americans. Methods This is a study of arterionephrosclerosis in successfully APOL1 -genotyped autopsy kidney tissue of 159 African Americans and 135 whites aged 18 to 89 years from a general population with no clinical renal disease. Results Glomerulosclerosis was nearly exclusively focal global Glomerulosclerosis with 3 subjects having focal segmental Glomerulosclerosis–like lesions that were unrelated to APOL1 risk status. For both races, in multivariable analysis, the dependent variables of arteriosclerosis and Glomerulosclerosis were significantly related to the independent variables of older age ( P P APOL1 genotype and arteriosclerosis was apparent only after 35 years of age, when, for any level of elevated blood pressure, more severe arteriosclerosis was found in the interlobular arteries of 14 subjects with 2 APOL1 risk alleles compared to African Americans with none ( n = 37, P = 0.02) or 1 risk allele ( n = 35, P = 0.02). Discussion With the limitation of the small number of subjects contributing to the positive results, the findings imply that APOL1 risk alleles recessively augment small-vessel arteriosclerosis in conjunction with age and hypertension. Focal segmental Glomerulosclerosis was not a significant finding, indicating that in the early stages of arterionephrosclerosis, the primary pathologic influence of APOL1 genotype is vascular rather than glomerular.
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APOL1 Risk Alleles Are Associated With More Severe Arteriosclerosis in Renal Resistance Vessels With Aging and Hypertension
Elsevier, 2016Co-Authors: Michael D Hughson, Susan A Mott, Victor G Puelles, John F Bertram, Cheryl A Winkler, Wendy E. Hoy, Jeffrey B. KoppAbstract:The increased risk of end-stage kidney disease among hypertensive African Americans is partly related to APOL1 allele variants. The initial Glomerulosclerosis of hypertension-associated arterionephrosclerosis consists of focal global Glomerulosclerosis, but in biopsy studies, focal segmental Glomerulosclerosis is found with progression to end-stage kidney disease, particularly in African Americans. Methods: This is a study of arterionephrosclerosis in successfully APOL1-genotyped autopsy kidney tissue of 159 African Americans and 135 whites aged 18 to 89 years from a general population with no clinical renal disease. Results: Glomerulosclerosis was nearly exclusively focal global Glomerulosclerosis with 3 subjects having focal segmental Glomerulosclerosis–like lesions that were unrelated to APOL1 risk status. For both races, in multivariable analysis, the dependent variables of arteriosclerosis and Glomerulosclerosis were significantly related to the independent variables of older age (P < 0.001) and hypertension (P < 0.001). A relationship between APOL1 genotype and arteriosclerosis was apparent only after 35 years of age, when, for any level of elevated blood pressure, more severe arteriosclerosis was found in the interlobular arteries of 14 subjects with 2 APOL1 risk alleles compared to African Americans with none (n = 37, P = 0.02) or 1 risk allele (n = 35, P = 0.02). Discussion: With the limitation of the small number of subjects contributing to the positive results, the findings imply that APOL1 risk alleles recessively augment small-vessel arteriosclerosis in conjunction with age and hypertension. Focal segmental Glomerulosclerosis was not a significant finding, indicating that in the early stages of arterionephrosclerosis, the primary pathologic influence of APOL1 genotype is vascular rather than glomerular
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TGF-beta1 reduces Wilms' tumor suppressor gene expression in podocytes
Nephrology Dialysis Transplantation, 2011Co-Authors: Toru Sakairi, Yoshifusa Abe, Jeffrey B. KoppAbstract:Background. Wilms' tumor suppressor gene (WT1) is essential for normal podocyte function, and transforming growth factor (TGF)-beta contributes to focal segmental Glomerulosclerosis (FSGS). We aimed to address whether TGF-beta affects WT1 expression in podocytes. Methods. A human podocyte cell line treated with TGF-beta1 and kidneys in Alb/TGF-beta1-transgenic mice were analyzed for WT1 expression. Results. In cultured podocytes, TGF-beta1 reduced WT1 protein expression determined by western blotting beginning at 8 h and decreased WT1 messenger RNA (mRNA) expression measured by quantitative reverse transcription–polymerase chain reaction beginning at 3 h. Knockdown of Smad4 by small hairpin (sh) RNA partially rescued the TGF-beta1-induced reduction of both WT1 protein and mRNA expressions in the cultured podocytes. TGF-beta1 did not alter luciferase activity of the reporter construct for a human WT1 promoter but reduced that for a human WT1 5′ enhancer construct, suggesting that TGF-beta1 may regulate WT1 expression by altering the 5′ enhancer activity. In the transgenic mice, WT1 protein expression in podocytes was decreased at 1 and 3 weeks of age, while glomeruloclerosis developed after 3 weeks. Conclusion. TGF-beta1 reduces WT1 expression in cultured human podocytes and podocytes in mice before overt Glomerulosclerosis begins. The effects are at least partially Smad4 dependent. Our findings identify a novel pathway linking TGF-beta1 to podocyte injury and FSGS. The WT1 reduction may be a useful marker for early podocyte injury.
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NPHS2 gene, nephrotic syndrome and focal segmental Glomerulosclerosis: A HuGE review
Genetics in Medicine, 2006Co-Authors: Nora Franceschini, Jeffrey B. Kopp, Kari E North, Louise Mckenzie, Cheryl WinklerAbstract:Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental Glomerulosclerosis. Mutations in the podocin gene, NPHS2 , have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental Glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental Glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental Glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental Glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20–40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.
Alessia Fornoni - One of the best experts on this subject based on the ideXlab platform.
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The elusive podocyte crossmatch for recurrent focal segmental Glomerulosclerosis.
Kidney international, 2019Co-Authors: George W. Burke, Alessia FornoniAbstract:Focal segmental Glomerulosclerosis is a glomerular disorder with a high rate of recurrence. Although kidney biopsies remain the gold standard to diagnose recurrent focal segmental Glomerulosclerosis, non-invasive prognostic assays could facilitate preventive treatments and offer insight into disease pathogenicity and heterogeneity. Srivastava et al. describe a simple, cell-based assay to predict recurrence of focal segmental Glomerulosclerosis. Although the study needs to be optimized and validated, its novelty is that it does not depend on the specificity of a given permeability factor.
Lawrence B Holzman - One of the best experts on this subject based on the ideXlab platform.
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background strain and the differential susceptibility of podocyte specific deletion of myh9 on murine models of experimental Glomerulosclerosis and hiv nephropathy
PLOS ONE, 2013Co-Authors: Duncan B. Johnstone, Omer Ikizler, Jidong Zhang, Lawrence B HolzmanAbstract:We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to Glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous Glomerulosclerosis in mice on a mixed background, suggesting that the Glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9flox alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to Glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p>0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p<0.05 or less). In contrast, we found that PodΔMyh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that PodΔMyh9 results in a variable susceptibility to Glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of Glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes.
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podocyte depletion causes Glomerulosclerosis diphtheria toxin induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene
Journal of The American Society of Nephrology, 2005Co-Authors: Bryan L Wharram, Meera Goyal, Jocelyn Wiggins, Silja K Sanden, Sabiha Hussain, Wanda E Filipiak, Thomas L Saunders, Robert C Dysko, Kenji Kohno, Lawrence B HolzmanAbstract:Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and Glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental Glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global Glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, Glomerulosclerosis, and proteinuria seen in diabetic Glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving Glomerulosclerosis and progressive loss of renal function in human glomerular diseases.
Richard A Sidner - One of the best experts on this subject based on the ideXlab platform.
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resolution of recurrent focal segmental Glomerulosclerosis proteinuria after rituximab treatment
The New England Journal of Medicine, 2006Co-Authors: Mark D Pescovitz, B K Book, Richard A SidnerAbstract:To the Editor: Focal segmental Glomerulosclerosis recurs in about 30 percent of patients who undergo kidney transplantation for this condition and leads to the nephrotic syndrome and accelerated graft loss.1 Cyclosporine, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and mycophenolate mofetil have been variably effective.1,2 We report the case of a seven-year-old boy who presented with immediate recurrence of focal segmental Glomerulosclerosis after transplantation that subsequently resolved only after rituximab treatment of a transplantation-related lymphoma that occurred five months after the surgery. This child originally had biopsy-proven primary focal segmental Glomerulosclerosis with the nephrotic syndrome. After 4.5 years, he progressed to . . .
Agnes B. Fogo - One of the best experts on this subject based on the ideXlab platform.
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Effects of combination PPARγ agonist and angiotensin receptor blocker on Glomerulosclerosis
Laboratory Investigation, 2016Co-Authors: Keizo Matsushita, Hai-chun Yang, Manu M Mysore, Jianyong Zhong, Yu Shyr, Li-jun Ma, Agnes B. FogoAbstract:We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing Glomerulosclerosis. We also found that proliferator-activated recepto- γ (PPAR γ ) agonist can attenuate Glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established Glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate Glomerulosclerosis, and treated with ARB, PPAR γ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and Glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of Glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT_2 receptor and Mas1 mRNA in the combination group. PPAR γ agonists in combination with ARB augment regression of Glomerulosclerosis, with downregulation of injurious RAAS components vs PPAR γ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.
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glomerular sclerosis is prevented during urinary tract obstruction due to podocyte protection
American Journal of Physiology-renal Physiology, 2011Co-Authors: Taiji Matsusaka, Agnes B. Fogo, Kazuto Kobayashi, Ira Pastan, Iekuni IchikawaAbstract:Urine outflow obstruction activates a variety of profibrotic factors, including the intrarenal renin-angiotensin system. However, the obstruction also nullifies the transmural hydraulic pressure difference across the glomerular capillary wall, an established inducer of Glomerulosclerosis. In the present study, we investigated whether, and by what mechanism, urine outflow obstruction affects the process of progressive Glomerulosclerosis. For this purpose, we tested the effect of unilateral ureteral obstruction (UUO) of 7 days duration in two distinct mouse models of Glomerulosclerosis. In the human immunodeficiency virus (HIV) nephropathy model, where HIV-1 genes are selectively expressed in podocytes and develop progressive podocyte damage and Glomerulosclerosis, UUO protected against sclerosis with preservation of podocytes morphologically and immunohistochemically. In contrast, the nonobstructed contralateral kidneys of these mice, as well as sham-operated HIV-1 mouse kidneys, developed severe podocyte injury and Glomerulosclerosis. The protection against Glomerulosclerosis imparted by ureteral obstruction was also documented in the NEP25 model of podocyte injury, in which a single injection of immunotoxin, LMB2, triggers selective podocyte injury followed by Glomerulosclerosis, both of which were protected by UUO. Notably, intervention with an angiotensin II type 1 receptor antagonist provided only a partial protective effect in each of the models. These results demonstrate that urine outflow obstruction protects the glomerulus from progressive sclerosis. The results further reveal that this protection occurs at a very early stage of the pathologic process, namely, damage of podocytes.
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Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Jean Claude Aldigier, Talerngsak Kanjanbuch, Nancy J. Brown, Agnes B. FogoAbstract:In this study, the effects of inhibition of aldosterone on regression of existing hypertension-related Glomerulosclerosis were investigated. Adult male Sprague Dawley rats (220 to 250 g) underwent 5/6 nephrectomy (Nx). Severity of Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equal biopsy sclerosis and then randomized by group to 4-wk treatments as follows: Control with no further treatment (CONT; n = 6); spironolactone (SP) alone (200 mg/kg per d, by gavage, n = 6); or SP combined with nonspecific triple antihypertensive drugs (TRX; reserpine, hydralazine, and hydrochlorothiazide in drinking water; SP+TRX, n = 7) or with angiotensin type 1 receptor antagonist (AT1RA; losartan in drinking water; SP+AT1RA, n = 8). When the rats were killed 12 wk after Nx, autopsy Glomerulosclerosis index (SI; 0 to 4+ scale) was compared with biopsy SI in the same rats. Systolic BP was increased at 8 wk after Nx and continued to increase at 12 wk after Nx in the CONT and SP groups but not in SP+TRX- or SP+AT1RA-treated rats. Serum creatinine at 12 wk was significantly decreased in all SP-treated groups versus CONT. CONT rats had on average a 157% increase in SI from biopsy to killing at 12 wk, compared with only 84% increase in SP rats, with regression of SI in some rats. The effects on Glomerulosclerosis by SP were further enhanced (when systolic BP was controlled by TRX or by AT1RA). It is concluded that inhibition of aldosterone by SP not only slows development of Glomerulosclerosis but also induces regression in some rats of existing Glomerulosclerosis.
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Is focal segmental Glomerulosclerosis really focal? Distribution of lesions in adults and children.
Kidney International, 1995Co-Authors: Agnes B. Fogo, Alan D. Glick, Sarah L. Horn, Robert G. HornAbstract:Is focal segmental Glomerulosclerosis really focal? Distribution of lesions in adults and children. The distribution of lesions of Glomerulosclerosis, whether focal or diffuse, has important implications for pathogenesis and potential therapeutic response. Determination of focal or diffuse nature of lesions from a single section, may, however, be misleading. We therefore evaluated the distribution of segmental Glomerulosclerosis in patients with nephrotic syndrome and idiopathic focal segmental Glomerulosclerosis (FSGS) by three-dimensional analysis. From our files, we identified all such biopsies with a diagnosis established by immunofluorescence, electron microscopy, and light microscopy that had >10 glomeruli and serum creatinine
