title: Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman's capsule in diabetes.
abstract: The metabolic and hemodynamic alterations in diabetes activate podocytes to increase extracellular matrix (ECM) production, leading to thickening of the glomerular basement membrane (GBM). We hypothesized that diabetes would activate parietal epithelial cells (PECs) in a similar manner and cause thickening of Bowman's capsules. Periodic acid Schiff staining of human kidney biopsies of 30 patients with diabetic nephropathy (DN) revealed a significantly thicker Bowman's capsule as compared with 20 non-diabetic controls. The average thickness was 4.55±0.21 μm in the group of patients with DN compared with 2.92±0.21 μm in the group of non-diabetic controls (P<0.001). Transmission electron microscopy confirmed this finding. In vitro, short-term exposure of human PECs to hyperglycemic conditions (30 mM glucose) advanced glycation end products (100 μg/ml) or transforming growth factor-β1 (TGF-β1; 5 ng/ml) increased the mRNA expression of collagen type I α-1, collagen type IV (all six α-chains), bamacan, nidogen 1, laminin α-1, and perlecan. Western blot and colorimetric collagen assays confirmed these results for collagen type IV at the protein level. The production and secretion of TGF-β1 as a possible positive feedback loop was excluded as a mechanism for the autocrine activation of human PECs. To validate these findings in vivo, activation of the PECs was assessed by immunohistochemical staining for CD44 of 12 human biopsy cases with DN. Thickening of the Bowman's capsule showed strong association with CD44-positive PECs. In summary, metabolic alterations in diabetes activate PECs to increase the expression and secretion of Bowman's capsule proteins. This process may contribute to the thickening of the Bowman's capsule, similar to the thickening of the GBM that is driven by activated podocytes. These data may also imply that activated PECs contribute to ECM production once they migrate to the glomerular tuft, a process resulting in glomerular scaring, for example, in diabetic glomerulosclerosis.
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Holderied
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Romoli
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Eberhard
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Konrad
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Devarapu
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Marschner
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians Universität, München, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Müller
authors.affiliation: Nephrologisches Zentrum der LMU, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität München, München, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000328:Adult; D015153:Blotting, Western; D050476:Bowman Capsule / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000716127:COL1A1 protein, human; D000090602:Collagen Type I, alpha 1 Chain; D017127:Glycation End Products, Advanced; D018960:Hyaluronan Receptors; D053773:Transforming Growth Factor beta1; D003094:Collagen; D005947:Glucose