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PubMed1988

Peripolar cells in the avian kidney.

Four white leghorn chickens were injected with furosemide (20 mg per kg body weight) three times at 12 h intervals and the kidneys fixed by perfusion after 36 h. Five chickens were injected with DOCA (desoxycortone trimethylacetate, 75 mg per kg body weight) three times at 12 day intervals and the kidneys fixed by perfusion after 36 days. Serial sections from the kidneys of these two groups of birds were made and the number of peripolar cells recorded. These recordings were compared with the number of peripolar cells in four normal, untreated chickens. A significant increase in the number of peripolar cells was recorded in the furosemide treated group. No significant change was seen in the DOCA treated group. However, in the DOCA-group heavily granulated podocytes were found. No distinct morphological difference was found between the granules in the podocytes and the granules in the peripolar cells. A possible lysosomal nature of the peripolar cell granules is discussed.

Animals↗
PubMed1986

Distribution of endogenous albumin in the glomerular wall of streptozotocin-induced diabetic rats as revealed by high-resolution immunocytochemistry.

Endogenous albumin was revealed with high resolution in the glomerular wall of renal tissue from normoglycaemic and long-term streptozotocin-induced hyperglycaemic rats applying the protein A-gold immunocytochemical approach. In tissues from normal animals, albumin antigenic sites were detected at the level of the endothelial cell basal plasma membrane and in the subendothelial side of the lamina densa of the glomerular basal laminae. The epithelial side of the laminae was weakly labelled, while the urinary space was devoid of labelling. In the podocytes, labelling for albumin was confined to few lysosomal structures. In diabetic animals, concomitant with hyperglycaemy, low insulin levels, significant glycosuria, proteinuria and albuminuria, the glomerular basal laminae displayed the characteristic increase in thickness found in diabetic microangiopathy (404 +/- 45 nm versus 190 +/- 10 nm). Major basal laminae deposits were also found in the mesangial regions. Albumin antigenic sites were detected throughout the entire thickness of the glomerular basal laminae without any preferential accumulation at any particular site. Labelling was also found over flocculent material present in the urinary space. Numerous densely labelled lysosomal structures were present in the podocytes. The basal laminae deposits in the mesangial regions were labelled for albumin. Morphometrical evaluations made on the distribution of the labelling confirmed the qualitative observations. Two sites for albumin retention were revealed in the glomerular wall of the normal animal: the endothelial cell basal membrane (less than 10 nm) and the subendothelial side of the lamina densa (50 nm).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

[Molecular pathology of the glomerular sialoglycoprotein podocalyxin, a major component of the glomerular polyanion in experimental and human minimal glomerular change].

Visceral glomerular epithelial cells (or podocytes) are endowed with a highly polyanionic glycokalyx which is rich in sialic acid. We have identified a single sialoprotein - MW 140 kD - which we have called "Podocalyxin", and which is the major carrier of glomerular sialic acid. We have shown that podocalyxin of normal rat glomeruli contains 20 sialic acid residues per molecule, whereas in aminonucleoside nephrotic glomeruli only 4-5 sialic acid per molecule are present. We conclude that the loss of histochemical staining for the "glomerular polyanion" is due both to the reduction of sialic acid per podocalyxin molecule, and to the reduction of the surface of the podocyte's plasmalemma caused by spreading of footprocesses. We furtheron report that also in human glomeruli there is a sialoprotein which is distinct from rat podocalyxin in its electrophoretic mobility and immunological structure, but otherwise shows all features which are characteristic for rat podocalyxin.

Animals↗
PubMed1996

Analysis of WT1 gene expression during mouse nephrogenesis in organ culture.

The temporal and spatial expression patterns of the Wilms tumor gene, WT1, were studied during the organogenesis of the mouse kidney in vitro. In situ hybridization and immunocytochemistry localized cellular expression of WT1 in whole kidney organ cultures to the induced metanephric mesenchyme and developing podocytes. Organ cultures were further characterized immunocytochemically with antibodies that specifically labeled the different tubular epithelial components and supporting mesenchyme of the developing nephrons. In organ cultures, the WT1 expression pattern could be visualized in induced metanephric mesenchyme and entire cell cohorts of differentiating podocytes. Expression of WT1 and cell specific markers were retained in short-term monolayer cultures of dissociated kidneys. The development of the metanephric kidney in vitro involves a highly restricted temporal and spatial cellular expression pattern of WT1 which closely follows that observed in tissue sections from gestational kidney isolated during organogenesis in the mouse.

Animals↗
PubMed2003

[Pathogenetic aspectics of nephrotic syndrome].

Nephrotic syndrome is characterized by protein loss in the urine, hypoalbuminemia, hyperlipidemia and edema. Several diseases cause a nephrotic syndrome, as they damage the glomerular podocytes. These specialized epithelial cells, together with endothelial cells of the glomerular capillaries and the basal membrane, form a filter that retains plasma proteins in the circulation. A disturbance of this filter causes proteinuria. The three most common primary glomerular diseases are minimal change, membranous glomerulonephritis, and the primary focal segmental glomerulosclerosis. The familiar forms are rare; however, the identification of the relevant gene defects has greatly advanced our understanding of podocyte function as well as the pathogenesis of nephrotic syndrome.

Gene Expression Regulation↗
PubMed2002

Dynamic expression patterns of transforming growth factor-beta(2) and transforming growth factor-beta receptors in experimental glomerulonephritis.

Numerous studies have demonstrated the involvement of the transforming growth factor (TGF) isoform beta(1) in the pathogenesis of renal fibroproliferative diseases. Although in vitro studies suggest that TGF-beta(2) is equally potent to TGF-beta(1) in terms of its antimitogenic and fibrogenic effects, much less is known about the regulation of TGF-beta(2) in renal diseases associated with glomerular cell hyperplasia and matrix expansion. Here we investigated the glomerular expression patterns of TGF-beta(2) and of the TGF-beta receptors I, II, and III during the course of rat anti-Thy1.1 nephritis (days 2, 6, 12, and 56), a model characterized by transient mesangial hypercellularity and extracellular matrix accumulation. TGF-beta(2) exhibited dynamic changes in expression. Immunohistochemical double-staining of renal sections revealed that most TGF-beta(2)-positive cells in control glomeruli were podocytes with few TGF-beta(2)-positive mesangial cells. This staining pattern could also be observed in human kidney. On day 6 of anti-Thy1.1 nephritis both TGF-beta(2) positive podocytes and mesangial cells were more abundant. By western blot analysis of isolated glomeruli from nephritic rats, protein expression of TGF-beta(2) was upregulated tenfold over control glomeruli, peaking on day 6 of the disease. In cultured rat mesangial cells we found that the TGF-beta(2) and TGF-beta(1) isoforms were equally potent in terms of nuclear accumulation of phosphorylated Smad 2/3, inhibition of DNA synthesis, and induction of beta(1)-integrin and type I collagen protein synthesis. Protein expression of the TGF-beta receptor I was not detected by immunohistochemistry in control glomeruli but was markedly induced in the mesangium on day 6 of nephritis. Mesangial staining for TGF-beta receptors II and III was detected in normal kidneys. Expression of TGF-beta receptor II was strongly enhanced on days 6 and 12 of disease, while TGF-beta receptor III was upregulated only on day 6. In summary, we report marked yet transient upregulation of TGF-beta(2) protein and of TGF-beta receptors I, II, and III in glomerular cells during anti-Thy1.1 nephritis. These results are in keeping with the notion that TGF-beta(2) and its receptors participate in the pathogenesis and/or resolution of this transient form of glomerulonephritis.

Animals↗
PubMed2001

Initial pathological events in renal dysplasia with urinary tract obstruction in utero.

Multicystic dysplastic kidneys (MCDK) and obstructive renal dysplasia (ORD) are two different phenotypes of dysplasia commonly associated with urinary tract obstruction. However, the mechanisms whereby obstruction in the developing kidney leads to each dysplasia are unknown. In the present study, 16 fetal MCDKs and 3 fetal ORDs (18-35 weeks of gestation) were analyzed with light microscopy, point-counting morphometry, immunohistochemistry with a podocyte marker, and scanning electron microscopy. Additionally, reconstructions of dysplastic nephrons were done via serial section analysis. Early stages of MCDK and ORD similarly revealed numerous cyst formations, predominantly in the subcapsular nephrogenic zone. Occasionally, glomerular tuft remnants with mature podocyte phenotypes were observed in cysts, suggesting the acquisition of filtration. Three dimensionally, basic nephron structures were installed in the cystic nephrons, namely the macula densa with a primary loop structure. Cysts developed in the once-induced nephrons due to fluid retention in both MCDK and ORD. In utero urinary tract obstruction may cause urine retention in functioning nephrons and lead to glomerular cysts in the nephrogenic zone. These findings were common to MCDK and ORD, albeit at different sites of obstruction. Expansion of glomerular cysts with tubular dilatation (cysts) disturbs the subsequent nephrogenesis and may contribute to the misdevelopment of fetal kidneys.

Cysts↗
PubMed1998

A role of microtubules during the formation of cell processes in neuronal and non-neuronal cells.

This review discusses the role of microtubules in the formation of processes from neuronal and non-neuronal cells. In elongating axons of the neuron, tubulin molecules are transported toward the end of pre-existing microtubules, which may be nucleated at the centrosome, via a mechanism called slow axonal flow. Two different hypotheses are presented to explain this mechanism; the transport of soluble monomers and/or oligomers versus the transport of polymerized microtubules. The majority of tubulin seems to be transported as small oligomers as shown by the data presented so far. Alternatively, an active transport of polymerized microtubules driven by microtubule-based motor proteins is postulated as being responsible for the non-uniform polarity of microtubule bundles in dendrites of the neuron. Microtubule-associated proteins (MAPs) play a crucial role in stabilizing the microtubular arrays, whereas the non-uniform polarity of microtubules may be established with the aid of microtubule-based motor proteins. The signals activating centrosomal proteins and MAPs, resulting in process formation, include phosphorylation and dephosphorylation of these proteins. Not only neuronal cells, but also renal glomerular podocytes develop prominent cell processes equipped with well-organized microtubular cytoskeletons, and intermediate and actin filaments. A novel cell culture system for podocytes, in which process formation can be induced, should provide further evidence that microtubules play a pivotal role in process formation of non-neuronal cells.

Animals↗
PubMed2002

Embryonal hyperplasia of Bowman's capsular epithelium in patients with WT1 mutations.

Embryonal hyperplasia of Bowman's capsular epithelium (EHBCE) is a rare condition, observed in patients with end-stage renal disease when treated with long-term dialysis. Immunohistochemical studies have suggested that EHBCE originates from the visceral epithelium of the Bowman's capsule. Here we report two patients with WT1 missense mutations in exon 7, who received continuous ambulatory peritoneal dialysis and developed EHBCE without Wilms tumor. One patient showed manifestations of Denys-Drash syndrome (DDS), while the other patient exhibited rapid progress into end-stage renal disease, but no genitourinary anomaly. Recently, abnormal expression of WT1 and PAX2 was shown in the podocytes in diffuse mesangial sclerosis (DMS) associated with DDS and isolated DMS. We hypothesize that EHBCE is a reversion of Bowman's capsular epithelial cells to an earlier cell differentiation state, which has the characteristics of a progenitor cell of both Bowman's capsular epithelia and podocytes. Immunohistochemical analysis of WT1, PAX2, vimentin, cytokeratin, and epithelial membrane antigen was performed in the kidney specimens obtained at autopsy or surgery. Abnormal expression of WT1 and PAX2 in the EHBCE was observed in both patients, supporting our hypothesis. The nephropathy associated with constitutional WT1 mutations might therefore be associated with EHBCE.

Cell Differentiation↗
PubMed2005

Rapid development of glomerular injury and renal failure in mice lacking p53R2.

The Rrm2b gene encodes p53R2, a catalytic subunit of ribonucleotide reductase that is required for DNA repair. Embryonic stem (ES) cells containing a retroviral insertion in the Rrm2b locus were used to generate mutant mice. Analysis of kidney RNA from Rrm2b (-/-) mice showed that the retroviral insertion disrupted expression of Rrm2b transcripts. Rrm2b (-/-) pups were represented at the expected Mendelian ratios at 10-12 days of age and grew normally past weaning. Mice failed to thrive after 6 weeks of age and began to die by 8 weeks of age. Phenotyping revealed that Rrm2b (-/-) mice died from a severe glomerular lesion that led to nephrotic syndrome and chronic renal failure. In kidneys of Rrm2b (-/-) mice, podocytes were enlarged and there was evidence of foot process effacement by 6 weeks of age. By 8 weeks of age, progressive podocyte hypertrophy and loss of foot processes was accompanied by hypertrophy of glomerular capillary endothelial cells that was extensive enough to restrict capillary blood flow. Collapsing glomerulopathy with avascular glomeruli was widespread in mice surviving beyond 9 weeks of age. Additional abnormalities in other organ systems were minor or consistent with secondary effects of renal failure. These findings suggest that lack of p53R2, the protein encoded by Rrm2b, has early and relatively selective detrimental effects on the kidney glomerulus that lead to rapid death from progressive renal failure.

Animals↗
PubMed2005

Congenital nephrotic syndrome responsive to angiotensin-converting enzyme inhibition.

Congenital nephrotic syndrome is a severe disorder caused by increased permeability of the glomerular capillary leading to massive proteinuria. Typically, this disorder presents in the first three months and is caused by inherited mutations in genes encoding structural proteins of the podocyte slit membrane and, as such, is usually irreversible. Medical management is often insufficient to stem the enormous losses of protein, and the patients require nephrectomies. Here, we present results for a patient with congenital nephrotic syndrome of unknown etiology which responded to treatment with an angiotensin-converting enzyme inhibitor alone. The patient's proteinuria relapsed when the medication was stopped, but went into complete remission after restarting treatment. This remarkable response is discussed in the light of recent investigations into the effect of angiotensin II on podocyte integrity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Capillary and aortic endothelia interact in situ with nonenzymatically glycated albumin and develop specific alterations in early experimental diabetes.

Diabetic mice (6 weeks duration) were studied to assess the interaction of advanced glycation endproduct-modified albumin (AGE-Alb) with micro- and macrovascular endothelium, and to evaluate the alterations induced in the ultrastructure of the lung, kidney, and aorta. [125I]-AGE-Alb and AGE-Alb-Au were perfused in situ in the vasculature; the total uptake was quantitated by spectrometry, and the endothelial pathways of AGE-Alb-Au and the morphological alterations of the vascular beds were examined by electron microscopy. The results showed that [125I]-AGE-Alb (0.567 microM) was taken up specifically and saturably by all organs studied, and particularly by the lung. AGE-Alb-Au endocytosis and transcytosis occurred in the pulmonary and aortic endothelia, and were enhanced in diabetic animals. Also in diabetic animals, AGE-Alb-Au was detected throughout the kidney glomerular basement membrane (GBM) and within open filtration slits of podocytes, suggesting altered barrier function. The structural modifications progressed, and at the end of the experimental period, in the lung approximately 28% of the capillaries and approximately 25% of the alveoli became compressed or even collapsed, due to the hyperplasia of extracellular matrix and interstitial connective tissue. The presence of adherent intravascular macrophages suggests the development of an inflammatory immune process. The structural modifications observed in kidney glomeruli included thickening (approximately 30%) of the GBM and the disappearance of diaphragms between the cellular processes of podocytes. The aortic endothelium displayed luminal foldings, increased number (2.8-fold) of Weibel-Palade bodies, and proliferation of basal lamina. Together, the results show that in diabetes there is enhanced vascular uptake of AGE-Alb and significant pathomorphological changes of micro- and macrovessels.

Animals↗
PubMed1984

Incomplete fusion of the epithelial and endothelial basement membranes in interspecies hybrid glomeruli.

Avascular, undifferentiated mouse kidneys transplanted onto quail chorioallantoic membrane differentiate and become vascularized by quail vessels. The glomeruli which form under these conditions consist of mouse podocytes and quail endothelial cells. Immunohistochemistry has shown that the glomerular basement membrane (GBM) has a dual origin, as integral basement membrane components are produced by both podocytes and endothelial cells. In electron microscopy this GBM is composed of two partially separated layers, an epithelial and an endothelial basal lamina which both have a lamina densa and a lamina rara. These two basal laminas are partially fused, but there are large areas where this fusion does not occur. In some places of incomplete fusion, fibrillar extracellular material is seen between and beneath the GBM. It is concluded that basement membrane components derived from the different species can interact partially, but the fusion is incomplete. The abnormal assembly of the epithelial and the endothelial basal laminas might be due to molecular differences between the components produced by the two cell lineages. In spite of the incomplete fusion, the system used serves as a good model-system to study basement membrane formation, since the cells organize in a histiotypic fashion and form true vascularized glomeruli.

Animals↗
PubMedDate not supplied

Kinetic study of glomerular cells of diabetic rats in relation to the development of irreversible glomerular sclerosis.

In order to clarify the cellular kinetics involved in progression of diabetic glomerulosclerosis, the epithelial cells of spontaneously diabetic WBN/Kob rats were investigated by labeling with the DNA precursor bromodeoxyuridine, which was histochemically stained using monoclonal antibody. The labeling index (number of labeled cells/number of cells counted) of glomeruli was constantly low (approximately 0.15%) and no significant variation could be demonstrated in control rats of the Wistar strain. In both control and diabetic rats, podocytes showed no evidence of mitosis. In contrast to capillary podocytes, the Bowman epithelial cells of diabetic rats showed increased labeling, often surrounding sclerotic capillaries. These observations suggest a critical role of Bowman's epithelial cells in the development of irreversibly sclerotic glomeruli in diabetic nephropathy.

Animals↗
PubMed2005

Renal glomerular permselectivity and vascular endothelium.

The glomerular barrier is the kidney's physical block to the unrestricted flow of molecules from the plasma into the urinary space. Its exquisite selectivity allows solutes and water in the glomerular capillaries to pass through but it prevents the bulk of plasma proteins, most notably albumin, from crossing. Classically the barrier consists of three components: glomerular endothelium, glomerular basement membrane and glomerular epithelium (podocytes) with slit diaphragm. A lot of investigations are experimental but they are sufficient to show the pivotal role of endothelium in glomerular proteinuria. In this study the author discuss glomerular endothelium with particular emphasis on the barrier presumed to be imparted by endothelium-glomerular basement membrane-podocyte interactions. By specialized glomerular endothelial structure (caveolae, tight junctions, endothelium glycocalyx) and by circulating permeability factors (albumin, orosomucoid, apolipoproteins, Amadori's products). Concluding remarks underline the significance to study the glomerular vascular endothelial dysfunction.

Animals↗
PubMed2006

Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy.

Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH-IGF-IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH-IGF-IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.

Animals↗
PubMed2025

Liquid Biopsy-Multiomics Link Adhesion Pathway Dysregulation to Kidney Injury Severity.

INTRODUCTION: Severe acute kidney injury (AKI) is strongly associated with the risk of developing chronic kidney disease; however, little is known about the cell type-specific mechanisms driving kidney injury severity. METHODS: In this multicenter observational study, we used clinically obtained liquid biopsy proteomics and machine learning (ML) to predict severe outcomes in patients with COVID-associated and non-COVID AKI. Further, we orthogonally combined 169 urine proteomics with 437 plasma proteomics samples and 40 urine sediment single-cell transcriptomics samples to identify complementary dysregulated mechanisms. RESULTS: Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrate predictive power for both discovery and validation set with AUC of 87% and 76%, respectively. These predictive proteomics features obtained demonstrate that cell adhesion and autophagy-associated pathways are uniquely impacted in severe AKI. Differentially abundant proteins (DAPSs) associated with these pathways are highly expressed in cells of the juxtamedullary nephron, endothelial cells (ECs), and podocytes, indicating that these kidney cell types could be potential targets. Single-cell transcriptomic analysis in the in vitro model of kidney organoids infected with SARS-CoV-2 reveal dysregulation of extracellular matrix (ECM) organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters shows significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. CONCLUSION: Collectively, these data suggest that ECM degradation and adhesion-associated mechanisms could be the main driver of severe kidney injury.

AKI↗
PubMed2006

The Nephrotic Syndrome is an immunoinflammatory disorder.

The Nephrotic Syndrome is still a therapeutic and physiopathological challenge. The clinical response to systemic immunosuppression shows that an immunoinflammatory disorder supports the nephrotic syndrome. Experimental (in vitro and in vivo) studies show that proteinuria may induce kidney secretion of proinflammatory and profibrotic cytokines and subsequent renal inflammation mediated by leukocyte recruitment. In turn,the infiltrating leukocytes contribute to renal damage by releasing proinflammatory and profibrotic cytokines (kidney acute remodelling). Chronic proteinuria maintains continuous local cytokine secretion and leukocyte influx into the glomerulus or the interstitial space (kidney chronic remodelling). In glomerular injury (podocyte injury), proteinuria itself, as well as glomerular secreted cyotokines, stimulates downstream tubular epithelial cells to secrete cytokines,as well. The mutual stimulation between proteinuria-cytokines-podocyte dysfunction-infiltrating leukocytes supports progressive tubular damage, renal fibrosis and glomerulosclerosis. Interfering with the cytokine network by inhibition/blockade of the cytokine receptor and its synthesis (via NFkB and the JAK/STAT intracellular signalling pathway) may represent a promising therapeutic option for systemic immunosuppression. Renal cytokine escape into systemic circulation may provide to hypercytokinemia stress syndrome,which could help to explain the increase in efferent renal sympathetic nerve activity (physiopathological sympathetic overactivity) observed during experimental nephrotic edema.

Albumins↗