Abstract:We reported that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease, where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral-and 5/6 th nephrectomy models i… Show more
“…During the progression from MC to FSGS lesion, the glomeruli significantly increase their volumes and podocyte hypertrophy appears as a distinguishing feature of FSGS vs. MC ( Fogo et al, 1990 ). This would suggest that interventions aimed at regulating glomerular volume and podocyte hypertrophy could represent an effective strategy to sustain podocyte survival and to prevent podocytopenia ( Puelles et al, 2019 ; Banu et al, 2021 ). However, this adaptive response of podocytes is only sustainable until a threshold is reached, after which the podocyte detaches and progression to FSGS occurs.…”
Podocytopathies are a group of proteinuric glomerular disorders driven by primary podocyte injury that are associated with a set of lesion patterns observed on kidney biopsy, i.e., minimal changes, focal segmental glomerulosclerosis, diffuse mesangial sclerosis and collapsing glomerulopathy. These unspecific lesion patterns have long been considered as independent disease entities. By contrast, recent evidence from genetics and experimental studies demonstrated that they represent signs of repeated injury and repair attempts. These ongoing processes depend on the type, length, and severity of podocyte injury, as well as on the ability of parietal epithelial cells to drive repair. In this review, we discuss the main pathology patterns of podocytopathies with a focus on the cellular and molecular response of podocytes and parietal epithelial cells.
“…During the progression from MC to FSGS lesion, the glomeruli significantly increase their volumes and podocyte hypertrophy appears as a distinguishing feature of FSGS vs. MC ( Fogo et al, 1990 ). This would suggest that interventions aimed at regulating glomerular volume and podocyte hypertrophy could represent an effective strategy to sustain podocyte survival and to prevent podocytopenia ( Puelles et al, 2019 ; Banu et al, 2021 ). However, this adaptive response of podocytes is only sustainable until a threshold is reached, after which the podocyte detaches and progression to FSGS occurs.…”
Podocytopathies are a group of proteinuric glomerular disorders driven by primary podocyte injury that are associated with a set of lesion patterns observed on kidney biopsy, i.e., minimal changes, focal segmental glomerulosclerosis, diffuse mesangial sclerosis and collapsing glomerulopathy. These unspecific lesion patterns have long been considered as independent disease entities. By contrast, recent evidence from genetics and experimental studies demonstrated that they represent signs of repeated injury and repair attempts. These ongoing processes depend on the type, length, and severity of podocyte injury, as well as on the ability of parietal epithelial cells to drive repair. In this review, we discuss the main pathology patterns of podocytopathies with a focus on the cellular and molecular response of podocytes and parietal epithelial cells.
“…We also recently reported increased MGV in mice models with FSGS compared to the respective controls in each model 10 . Here we re-evaluated this data given the contribution of reduced shrinkage artefact seen in FSGS glomeruli to the reported glomerulomegaly reported in FSGS.…”
Section: Relating Mgv From Paraffin-based Techniques To Plastic-based...mentioning
confidence: 63%
“…To evaluate morphometry during significant glomerular injury, we used mice from two FSGS models performed in BALBc/J (n=10) - hypertrophic injury and a previously published ageing model [See methods 10,17 ]. The mice in these FSGS models had confirmed podocyte loss, glomerulosclerosis, proteinuria and azotemia 10,17 . In each animal, we evaluated three plastic-based morphometric techniques and three paraffin-based methods, comparing each with Vglom-Cav.…”
Section: Resultsmentioning
confidence: 99%
“…We used young male adult BALBc/J as controls (2-6 months age) for evaluating baseline morphometry (n=10). To evaluate morphometry with significant glomerular injury, we used mice from two FSGS models which were also performed in BALBc/J background(n=10) - hypertrophic injury and a previously published ageing model 10,17 . The FSGS lesions in these mice models were confirmed and characterized by a renal pathologist [representative images in Supplementary Figure].…”
Section: Methodsmentioning
confidence: 99%
“…Quantitative glomerular structural evaluation by morphometry has consistently revealed additional prognostic benefit over histology in human or experimental, diabetic-1,2 , or non-diabetic-glomerular disease [2][3][4][5][6][7][8][9] . For instance, we and others reported that FSGS was associated with larger glomerular volumes (Vglom) and podocyte hypertrophy, and that larger Vgloms predicted outcomes in human nephrotic syndromes 4,10 . Pathophysiologically, Vglom may reflect antecedent nephron injury and loss, with the consequent need for remaining nephrons (and glomeruli) to hypertrophy to increase the effective filtration surface area.…”
Morphometric estimates of mean glomerular volume (MGV) have clinical implications, over and above histologic data. However, MGV estimation is time-consuming, could waste tissue sections and requires expertise limiting its utility in retrospective clinical studies. Methods: We evaluated MGV using both plastic and paraffin-embedded tissue from control and FSGS mice (n=10 each) using the gold-standard Disector/Cavalieri technique (Vglom-Cav) and other reported techniques [2- or 3-profile technique, Weibel-Gomez method (W-G)]. Within Vglom-Cav we examined the precision of MGV estimation while using MGVs obtained from 5- or 10- individual glomeruli measurements vs the true mean (20 glomeruli). Results: In both FSGS and controls, we identified an acceptable precision of 10-glomerular sampling vs true MGV within Vglom-Cav technique [88 (79-94) % of MGV obtained were within 10% of the true MGV]. The 5-glomerular sampling was less precise [70 (56, 81) % of MGV obtained were within 10% of true MGV]. In plastic based techniques, 2- or 3-profile MGVs showed greater concordance with Vglom-Cav, than W-G MGV. The new 3-profile technique offered incremental benefit to the existing 2-profile method (improved Lins concordance in control and FSGS animals). We observed a consistent reduction of Vglom values within control animals (52+/-0.06%) in paraffin-embedded tissue (vs corresponding methods in plastic) demonstrating a clear shrinkage artefact due to tissue processing. FSGS glomeruli showed significantly less and more variable shrinkage artefact likely due to glomerular fibrosis. Conclusion: We report the precision of 5- or 10-glomerular sampling for MGV estimation using controls and FSGS animals. We demonstrate and quantify the shrinkage bias in MGV during tissue processing for paraffin-embedding that also differentiated control animals and FSGS. Our findings have implications for experimental studies using glomerular morphometry.
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