Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury

Systemic lupus erythematosus (SLE) is characterized by a broad spectrum of renal lesions. In lupus glomerulonephritis, histological classifications are based on immune-complex (IC) deposits and hypercellularity lesions (mesangial and/or endocapillary) in the glomeruli. However, there is compelling evidence to suggest that glomerular epithelial cells, and podocytes in particular, are also involved in glomerular injury in patients with SLE. Podocytes now appear to be not only subject to collateral damage due to glomerular capillary lesions secondary to IC and inflammatory processes, but they are also a potential direct target in lupus nephritis. Improvements in our understanding of podocyte injury could improve the classification of lupus glomerulonephritis. Indeed, podocyte injury may be prominent in two major presentations: lupus podocytopathy and glomerular crescent formation, in which glomerular parietal epithelial cells play also a key role. We review here the contribution of podocyte impairment to different presentations of lupus nephritis, focusing on the podocyte signaling pathways involved in these lesions.

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(Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/β-catenin pathways in glomerulonephritis

AJP Renal Physiology ◽

10.1152/ajprenal.00250.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F571-F578

Author(s):

Maki Urushihara ◽

Shuji Kondo ◽

Yukiko Kinoshita ◽

Natsuko Ozaki ◽

Ariunbold Jamba ◽

...

Keyword(s):

Cell Proliferation ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Mesangial Cells ◽

Macrophage Infiltration ◽

Crescent Formation ◽

Sirna Treatment ◽

Extracellular Signal ◽

Parietal Epithelial Cells

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

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Fibronectin mRNA and protein accumulation, distribution, and breakdown in rabbit anti-glomerular basement membrane disease.

Journal of the American Society of Nephrology ◽

10.1681/asn.v1121334 ◽

1991 ◽

Vol 1 (12) ◽

pp. 1334-1342

Author(s):

M Goyal ◽

R Wiggins

Keyword(s):

Basement Membrane ◽

Glomerular Basement Membrane ◽

Matrix Protein ◽

Interstitial Fibrosis ◽

Early Time ◽

Protein Accumulation ◽

Glomerular Injury ◽

Crescent Formation ◽

Mesangial Area ◽

Fibronectin Mrna

Fibronectin is a multifunctional matrix protein which by immunofluorescence appears to be present in increased amounts during glomerular injury. To examine fibronectin metabolism in glomerular injury, an anti-glomerular basement membrane model that progresses to severe glomerular crescent formation, glomerulosclerosis, and interstitial fibrosis was used. Fibronectin was purified from rabbit plasma, and a monoclonal antibody raised against rabbit fibronectin was used for immunolocalization and quantitation of fibronectin protein. RNA and protein were extracted from isolated glomeruli and whole renal cortex at various times during progression of disease. At day 4, there was a 2.5-fold increase in fibronectin protein which by immunofluorescence appeared to be in the glomerular mesangial area. There was no increase in glomerular fibronectin mRNA at this time. This discrepancy is consistent with the conclusion that, at this early time point, the increased glomerular fibronectin comes predominantly from plasma. By day 7, glomerular fibronectin mRNA and extractable fibronectin protein were increased in association with bright immunofluorescence along the inner aspect of Bowman's capsule where early crescents were forming. Similarly, at day 14, crescents stained very brightly for fibronectin. These results are consistent with the conclusion that, at later time points, fibronectin is synthesized in glomeruli in association with cell division and crescent formation. Degradation of fibronectin in glomerular and cortical extracts was demonstrated under normal and nephritic conditions by finding fibronectin proteolytic fragmentation by Western blot.(ABSTRACT TRUNCATED AT 250 WORDS)

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Suppression of anti-glomerular basement membrane nephritis by administration of anti-monocyte chemoattractant protein-1 antibody in WKY rats.

Journal of the American Society of Nephrology ◽

10.1681/asn.v871174 ◽

1997 ◽

Vol 8 (7) ◽

pp. 1174-1178

Author(s):

H Fujinaka ◽

T Yamamoto ◽

M Takeya ◽

L Feng ◽

K Kawasaki ◽

...

Keyword(s):

Basement Membrane ◽

Cross Section ◽

Glomerular Basement Membrane ◽

Suppressive Effect ◽

Glomerular Injury ◽

Crescent Formation ◽

Monocyte Chemoattractant Protein 1 ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Wky Rats

Anti-glomerular basement membrane (GBM) nephritis in WKY rats is characterized by an accumulation of CD8-positive lymphocytes (CD8+ lym) and monocytes/macrophages (Mo/M psi) in the glomeruli and crescent formation. In the study presented here, the involvement of a chemokine for Mo/M psi, monocyte chemoattractant protein-1 (MCP-1), was examined in this model. An intense induction of mRNA for MCP-1 in the glomeruli and a suppressive effect of anti-MCP-1 antibody administration on the glomerular Mo/M psi accumulation and proteinuria were found. MCP-1 mRNA was expressed intensely in the glomeruli 4 d after the anti-GBM antibody injection. When MCP-1 was neutralized with anti-MCP-1 antibody administration, the number of Mo/M psi infiltrating in the glomeruli decreased by 34.7% (19.6 +/- 7.1 versus 30.0 +/- 6.0 per glomerular cross-section, P < 0.01) and proteinuria by 66.2% (15.6 +/- 9.3 versus 46.1 +/- 15.1 mg/d, P < 0.01) at day 4. In contrast, the number of CD8+ lym accumulating in the glomeruli was not affected significantly (6.6 +/- 2.7 versus 6.0 +/- 3.0 per glomerular cross-section, P > 0.05). However, the treatment with the anti-MCP-1 antibody did not reduce Mo/M psi infiltration, urinary protein excretion, and crescent formation at day 8. These data suggest that MCP-1 plays a role in the glomerular accumulation of Mo/M psi, and that the infiltrating Mo/M psi cause glomerular injury and increased excretion of protein in the urine.

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Parietal epithelial cells role in repair versus scarring after glomerular injury

Current Opinion in Nephrology & Hypertension ◽

10.1097/mnh.0000000000000600 ◽

2020 ◽

Vol 29 (3) ◽

pp. 293-301 ◽

Cited By ~ 2

Author(s):

Hélène Lazareth ◽

Olivia Lenoir ◽

Pierre-Louis Tharaux

Keyword(s):

Epithelial Cells ◽

Glomerular Injury ◽

Parietal Epithelial Cells

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Subtotal Ablation of Parietal Epithelial Cells Induces Crescent Formation

Journal of the American Society of Nephrology ◽

10.1681/asn.2011050449 ◽

2012 ◽

Vol 23 (4) ◽

pp. 629-640 ◽

Cited By ~ 44

Author(s):

Eva-Maria Sicking ◽

Astrid Fuss ◽

Sandra Uhlig ◽

Peggy Jirak ◽

Henry Dijkman ◽

...

Keyword(s):

Epithelial Cells ◽

Crescent Formation ◽

Parietal Epithelial Cells

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Ovine Mesangiocapillary Glomerulonephritis Type I and Crescent Formation

Veterinary Pathology ◽

10.1177/030098589002700104 ◽

1990 ◽

Vol 27 (1) ◽

pp. 26-34 ◽

Cited By ~ 10

Author(s):

P. F. Frelier ◽

D. L. Armstrong ◽

J. Pritchard

Keyword(s):

Basement Membrane ◽

Glomerular Basement Membrane ◽

Inflammatory Cells ◽

Suitable Model ◽

Type I ◽

Human Beings ◽

Crescent Formation ◽

Mesangiocapillary Glomerulonephritis ◽

Bowman's Capsule

Morphologic examination of four Finnish Landrace mixed-breed lambs, 27 to 35 days of age, affected with mesangiocapillary glomerulonephritis type 1, demonstrated a progressive glomerulonephritis. By 27 days of age, three lambs had crescents in 58 to 93% of glomeruli. These three lambs were also uremic. The accelerated rate of crescent formation was attributed to infiltrating polymorphonuclear leukocytes and monocytes, the result of discontinuities (gaps) in the glomerular basement membrane, and to the loss of the integrity of Bowman's capsule. In the three lambs, platelets were identified adjacent to the endothelium or denuded glomerular basement membrane. Two distinctly different types of crescents were noted, apparently dependent on the integrity of Bowman's capsule. One type resulted from the influx of inflammatory cells and dissociation of parietal epithelial cells from Bowman's capsule. The other type was more extensive and contained collagen and was associated with damage to Bowman's capsule resulting in cellular infiltration from the interstitium and sclerosis. Based on morphologic similarities, ovine mesangiocapillary glomerulonephritis is a suitable model for studying the pathogenesis and treatment of mesangiocapillary glomerulonephritis type 1 in human beings.

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The renal glomerulus

10.1093/med/9780199592548.003.0043 ◽

2015 ◽

Author(s):

Marlies Elger ◽

Wilhelm Kriz

Keyword(s):

Epithelial Cells ◽

Mesangial Cells ◽

Juxtaglomerular Apparatus ◽

Cell Types ◽

Stem Cell Population ◽

Glomerular Filtration Barrier ◽

Crescent Formation ◽

Filtration Barrier ◽

Parietal Epithelial Cells ◽

Bowman's Capsule

The glomerulus performs its functions with three major cell types. Endothelial cells and visceral epithelial cells (podocytes) lie on the inside and outside of the glomerular basement membrane, and together these three structures form the glomerular filtration barrier. Mesangial cells sit in the axial region. Pathologies of all these regions and cell types can be identified. Parietal epithelial cells lining Bowman’s capsule participate in crescent formation, and at the tubular pole some of these cells seem to represent a stem cell population for tubular cells and podocytes. The extraglomerular mesangium and juxtaglomerular apparatus complete the description of the glomerular corpuscle. The structure of these elements, and how they relate to function, are illustrated in detail.

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Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21196978 ◽

2020 ◽

Vol 21 (19) ◽

pp. 6978

Author(s):

Foteini Moschovaki-Filippidou ◽

Stefanie Steiger ◽

Georg Lorenz ◽

Christoph Schmaderer ◽

Andrea Ribeiro ◽

...

Keyword(s):

T Cells ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Transforming Growth Factor ◽

Protective Effects ◽

Crescent Formation ◽

Activated T Cells ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Deficient Mice

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.

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