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İzmir, Turkey

Romagnani P.,University of Florence | Romagnani P.,Pediatric Nephrology Unit
Journal of Pathology | Year: 2013

Regeneration can occur through multiple distinct mechanisms, such as pluripotent stem cells, lineage-committed progenitors or dedifferentiation. The respective contribution of each of these regenerative strategies in every organ or tissue may be different. Recent results indicate that dedifferentiation contributes less than previously thought, and that stem or progenitor cells seem to be the main drivers of regenerative processes. Our views of regeneration in the kidney are undergoing the same process of revision. Indeed, studies in humans have established the existence of a scattered population of tubular progenitors in the adult kidney. Renal progenitors have been discovered also in other animal classes such as fish and insects. In contrast, in rodents a tubular progenitor phenotype seems to be induced only after tubular injury, suggesting some differences may exist. Is this difference really related to a distinct regenerative strategy or is it simply a matter of the type and modality of cellular markers expressed? It may also be possible that progenitor cells, as well as tubular cell dedifferentiation, act in concert to allow regeneration of a complex organ like the adult mammalian kidney, as recently proposed also for the liver. Further studies are needed to resolve the riddle of tubular regeneration. However, beyond the controversial results obtained from humans and rodents, identification of tubular progenitors in humans can move the field forward and provide a novel perspective for understanding tubular regeneration. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source


Liapis H.,University of Washington | Romagnani P.,Excellence Center for Research | Romagnani P.,Pediatric Nephrology Unit | Anders H.-J.,Ludwig Maximilians University of Munich
American Journal of Pathology | Year: 2013

Podocytes represent an essential component of the kidney's glomerular filtration barrier. They stay attached to the glomerular basement membrane via integrin interactions that support the capillary wall to withstand the pulsating filtration pressure. Podocyte structure is maintained by a dynamic actin cytoskeleton. Terminal differentiation is coupled with permanent exit from the cell cycle and arrest in a postmitotic state. Postmitotic podocytes do not have an infinite life span; in fact, physiologic loss in the urine is documented. Proteinuria and other injuries accelerate podocyte loss or induce death. Mature podocytes are unable to replicate and maintain their actin cytoskeleton simultaneously. By the end of mitosis, cytoskeletal actin forms part of the contractile ring, rendering a round shape to podocytes. Therefore, when podocyte mitosis is attempted, it may lead to aberrant mitosis (ie, mitotic catastrophe). Mitotic catastrophe implies that mitotic podocytes eventually detach or die; this is a previously unrecognized form of podocyte loss and a compensatory mechanism for podocyte hypertrophy that relies on post-G1-phase cell cycle arrest. In contrast, local podocyte progenitors (parietal epithelial cells) exhibit a simple actin cytoskeleton structure and can easily undergo mitosis, supporting podocyte regeneration. In this review we provide an appraisal of the in situ pathology of mitotic catastrophe compared with other proposed types of podocyte death and put experimental and renal biopsy data in a unified perspective. Copyright © 2013 American Society for Investigative Pathology. Source


Lasagni L.,University of Florence | Lazzeri E.,University of Florence | Shankland S.J.,University of Washington | Anders H.-J.,Ludwig Maximilians University of Munich | And 2 more authors.
Current Molecular Medicine | Year: 2013

Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future. © 2013 Bentham Science Publishers. Source


Debiec H.,University Pierre and Marie Curie | Lefeu F.,University Pierre and Marie Curie | Kemper M.J.,University of Hamburg | Niaudet P.,University of Paris Descartes | And 4 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: The M-type phospholipase A 2 receptor (PLA 2R) was recently identified as a candidate antigen in 70% of cases of idiopathic membranous nephropathy, a common form of the nephrotic syndrome. The nature of antigens involved in other idiopathic and secondary membranous nephropathies remains unclear. METHODS: We searched for antibodies against bovine serum albumin and circulating bovine serum albumin by means of enzyme-linked immunosorbent assay and Western blotting in serum specimens obtained from 50 patients with membranous nephropathy and 172 controls. The properties of immunopurified circulating bovine serum albumin obtained from serum specimens were analyzed with the use of two-dimensional sodium dodecyl sulfate-polyacrylamide-gel electrophoresis. We detected bovine serum albumin in glomerular deposits and analyzed the reactivity of eluted IgG. RESULTS: Eleven patients, including four children, had high levels of circulating anti-bovine serum albumin antibodies, of both the IgG1 and IgG4 subclasses. These patients also had elevated levels of circulating bovine serum albumin, without an increase in circulating immune complex levels. Bovine serum albumin immunopurified from the serum specimens of these four children migrated in the basic range of pH, whereas the bovine serum albumin from adult patients migrated in neutral regions as native bovine serum albumin. Bovine serum albumin was detected in subepithelial immune deposits only in the children with both high levels of cationic circulating bovine serum albumin and bovine serum albumin-specific antibodies, and it colocalized with IgG in the absence of PLA2R. IgG eluted from such deposits was specific for bovine serum albumin. CONCLUSIONS: Some patients with childhood membranous nephropathy have both circulating cationic bovine serum albumin and anti-bovine serum albumin antibodies. Bovine serum albumin is present in immune deposits, suggesting that cationic bovine serum albumin is pathogenic through binding to the anionic glomerular capillary wall and in situ formation of immune complexes, as shown in experimental models. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Source


Alconcher L.F.,Pediatric Nephrology Unit | Tombesi M.M.,Hospital Interzonal General de Agudos Dr Jose Penna
Pediatric Nephrology | Year: 2012

Background The purpose of this study was to assess the prevalence and outcome of newborns with bilateral mild isolated antenatal hydronephrosis managed with neither antibiotic prophylaxis nor voiding cystourethrography (VCUG). Methods Inclusion criteria were ultrasonographic evidence of an anterior-posterior pelvic diameter (APPD) of 5- 15 mm at the third trimester of gestation and on the first postnatal ultrasound sonogram. Exclusion criteria were an APPD>15 mm, calyectasis, hydroureteronephrosis, or renal or bladder abnormalities. Ultrasound follow-up was performed. Parents were familiarized with the signs of urinary tract infection (UTI). If UTI was confirmed, VCUG was performed. The outcome was assessed as intrauterine resolution of hydronephrosis, total or partial resolution, stability, or progression. Results Hydronephrosis was bilateral in 98 of the 236 newborns (196 hydronephrotic kidneys) with mild isolated antenatal hydronephrosis enrolled in this study. Nine patients had UTI, and none showed reflux. After a mean follow-up of 15 months, 74 kidneys showed intrauterine resolution (38%), 82 (42%) showed total resolution, 13 showed partial resolution, 24 were stable, and 3 showed progression. Bilateral cases represented 42% of mild isolated antenatal hydronephrosis. During the first year of life, 80% of the kidneys showed total hydronephrosis resolution, 9% of patients had UTI, and none of the patients showed reflux. Conclusions Antibiotic prophylaxis and VCUG are not mandatory in newborns with bilateral mild isolated antenatal hydronephrosis, but clinical and ultrasound follow-up are recommended during the first year of life. © 2011 IPNA. Source

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