Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman's capsule in diabetes

Holderied, Alexander; Romoli, Simone; Eberhard, Jonathan N.; Konrad, Lukas; Devarapu, Satish Kumar; Marschner, Julian A.; Müller, Susanna; Anders, Hans‐Joachim

doi:10.1038/labinvest.2014.160

Cited by 37 publications

(45 citation statements)

References 30 publications

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“…CD44 increased markedly in PECs in FSGS in CD44 +/+ mice, coinciding with increased collagen IV staining, consistent with previous reports. 1,19–22,7 These associations suggested, but did not prove, CD44 is linked with increased matrix accumulation. Thus, to prove glomerulosclerosis is lower in mice lacking CD44, we utilized CD44 −/− mice.…”

Section: Discussionmentioning

confidence: 91%

“…7 Figure 2G shows collagen IV quantification, and Figures 2H–M show representative images. Collagen IV staining was similar at baseline in CD44 +/+ and CD44 −/− mice along Bowman’s capsule, within the mesangium and tubular basement membranes (Figure 2H & K).…”

Section: Resultsmentioning

confidence: 99%

“…4 PECs are pivotal in forming the pathognomonic bridge (synechial attachment) between Bowman’s capsule and the glomerular tuft in FSGS, considered an initial podocyte disorder. 5 Studies show that PEC derived extracellular matrix increase in FSGS, 1, 6 diabetes 7 and the aging kidney, 4 contributing to glomerular scarring. Several extracellular matrix proteins also co-localize to PECs in aged kidneys.…”

Section: Introductionmentioning

confidence: 99%

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Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

Roeder

Barnes

Lee

et al. 2017

Kidney International

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The glycoprotein CD44 is barely detected in normal mouse and human glomeruli, but is increased in glomerular parietal epithelial cells following podocyte injury in focal segmental glomerulosclerosis (FSGS). To determine the biological role and regulation of CD44 in these cells, we employed an in vivo and in vitro approach. Experimental FSGS was induced in CD44 knockout and wildtype mice with a cytotoxic podocyte antibody. Albuminuria, focal and global glomerulosclerosis (periodic acid-Schiff stain) and collagen IV staining were lower in CD44 knockout compared with wild type mice with FSGS. Parietal epithelial cells had lower migration from Bowman’s capsule to the glomerular tuft in CD44 knockout mice with disease compared with wild type mice. In cultured murine parietal epithelial cells, overexpressing CD44 with a retroviral vector encoding CD44 was accompanied by significantly increased collagen IV expression and parietal epithelial cells migration. Because our results showed de novo co-staining for activated ERK1/2 (pERK) in parietal epithelial cells in experimental FSGS, and also in biopsies from patients with FSGS, two in vitro strategies were employed to prove that pERK regulated CD44 levels. First, mouse parietal epithelial cells were infected with a retroviral vector for the upstream kinase MEK-DD to increase pERK, which was accompanied by increased CD44 levels. Second, in CD44 overexpressing parietal epithelial cells, decreasing pERK with U0126 was accompanied by reduced CD44. Finally, parietal epithelial cell migration was higher in cells with increased and reduced in cells with decreased pERK. Thus, pERK is a regulator of CD44 expression and increased CD44 expression leads to a pro-sclerotic and migratory parietal epithelial cells phenotype.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

Roeder

Barnes

Lee

et al. 2017

Kidney International

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“…However, evidence in recent years indicates that podocytes are critical cells for maintaining the renal filtration barrier and preventing albuminuria, playing an important role in the development of renal diseases [4-6]. Podocyte damage, such as alterations in the structure of podocytes or loss of podocytes will affect the integrity of the glomerular filtration barrier, resulting in proteinuria, thus promoting the progression of DN [7, 8]. Accumulating evidence indicates that DN is more like a “podocyte disease” [9-11].…”

Section: Introductionmentioning

confidence: 99%

Swiprosin-1 Promotes Mitochondria-Dependent Apoptosis of Glomerular Podocytes via P38 MAPK Pathway in Early-Stage Diabetic Nephropathy

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Podocyte injury, especially podocyte apoptosis, plays a major role in early-stage diabetic nephropathy (DN). Swiprosin-1, also known as EF hand domain containing 2 (EFhd2), is a Ca²⁺-binding protein in different cell types. However, the function of swiprosin-1 in podocytes remains unknown. Methods: The expression and distribution of swiprosin-1 were investigated in the mouse renal glomerulus and conditionally immortalized mouse podocyte cell line MPC-5. The expression of swiprosin-1 was also detected in streptozotocin (STZ)-treated mice and MPC-5 cells treated with high glucose (HG). Nephrin and podocin were detected by immunohistochemistry and immunofluroscence. Collagen IV, transforming growth factor-β (TGF-β) and fibronectin mRNA expressions were assayed by real-time PCR. Apoptotic proteins and phosphorylation of p38 mitogen-activated protein kinase (MAPK) were detected by immunoblotting. Results: Swiprosin-1 was found to be expressed in podocytes of the mouse glomerulus and MPC-5 cells. Swiprosin-1 expression was increased in STZ-treated mice and MPC-5 cells treated with HG. In Swiprosin-1-/- diabetic mice, kidney/ body weight, urinary albumin, podocyte foot process effacement and glomerular basement membrane thickening were attenuated; the downregulation of nephrin and podocin expression in the glomerulus was inhibited; and the upregulation of collagen IV, TGF-β and fibronectin mRNA expression in the renal cortex was ameliorated as compared with those in diabetic swiprosin-1+/+ mice. In addition, the increased apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation in Swiprosin-1-/- diabetic mice were inhibited as compared with those in diabetic swiprosin-1+/+ mice. Knockdown of swiprosin-1 in MPC-5 cells reduced the apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation induced by HG. Targeted knockdown of p38 attenuated the increased apoptosis of MPC-5 cells over-expressing swiprosin-1. Conclusion: Swiprosin-1 expression in podocytes of the mouse glomerulus played a critical role in early-stage DN. Swiprosin-1 deficiency in early DN attenuated mitochondria-dependent podocyte apoptosis induced by hyperglycemia or HG via p38 MAPK signaling pathway.

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“…We had not studied Bowman's capsule nor vasculature (vasa afferentia/efferentia), however, it was obvious that important morphologic changes occurred also there (arteriolar hyaline lesions, fi brin-cap or exudative lesions, capsular drop lesions) (12). It is indisputable that the current mainstream research is concentrated on pathomorphology and pathophysiology on the molecular level.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Ultrastructural changes of kidney in diabetic rats

Miko¹,

Jakubovský²,

Vrabcova³

et al. 2016

BLL

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OBJECTIVES: To demonstrate histopathological changes in diabetic kidneys of the rat on ultrastructural level with focusing on glomerular cellular environment. METHODS: Male Wistar rats were administered streptozotocin and after 8 weeks, their kidneys were studied using qualitative transmission electron microscope analysis. RESULTS: In diabetic kidneys, the presence of irregularly thickened glomerular membrana basalis (GBM), often up to six times as compared to healthy kidney GBM, mainly around peripheral capillary loops, was striking. We also demonstrated lamination and split appearance of GBM, with presence of delicate fi brillar structure, which was absent within normal GBM. Accumulation of mesangial matrix was found only occasionally. CONCLUSION: Model may be useful to better understand the mechanisms that play role in the progression of DM-induced renal disease and to comprehend the morphological changes, which this process leaves within the tissue. The clear association between ultra-structure and functional markers may not be necessary (Fig. 4, Ref. 27). Text in PDF www.elis.sk.

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Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman's capsule in diabetes

Cited by 37 publications

References 30 publications

Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

Swiprosin-1 Promotes Mitochondria-Dependent Apoptosis of Glomerular Podocytes via P38 MAPK Pathway in Early-Stage Diabetic Nephropathy

Ultrastructural changes of kidney in diabetic rats

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