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Publications (75)
Background:
Parietal epithelial cells are a heterogeneous population of cells located on Bowman's capsule. These cells are known to internalize albumin with a still undetermined mechanism, although albumin has been shown to induce phenotypic changes in parietal epithelial cells. Proximal tubular cells are the main actors in albumin handling via th...
We report the case of two siblings with incomplete Donnai‐Barrow syndrome (DBS) phenotype carrying three LRP2 variants never associated before with DBS phenotype. image
Dent disease (DD1) is a rare tubulopathy caused by mutations in the CLCN5 gene. Glomerulosclerosis was recently reported in DD1 patients and ClC-5 protein was shown to be expressed in human podocytes. Nephrin and actin cytoskeleton play a key role for podocyte functions and podocyte endocytosis seems to be crucial for slit diaphragm regulation. The...
Dent disease is a rare X-linked renal tubulopathy due to CLCN5 and OCRL (DD2) mutations. OCRL mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of repo...
Background and Aims
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in older white adults, with an incidence of 12 cases per millions of people per year. Primary MN (PMN, 75%-80% of MNs) is an organ-specific autoimmune disease caused by antibodies anti-PLA2R and anti-THSD7A. Regardless of treatment one third of patients p...
Fabry disease is an X-linked disorder due to mutations in α-galactosidase A, resulting in the accumulation of enzyme substrates and cell malfunction. Kidney involvement is frequent, affecting all native kidney cell types. Podocyte damage results in proteinuria and chronic kidney disease. End-stage kidney disease is the rule in middle-aged males and...
ClC-5, the electrogenic chloride/proton exchanger strongly expressed in renal proximal tubules, belongs to the endocytic macromolecular complex responsible for albumin and low-molecular-weight protein uptake. ClC-5 was found to be overexpressed in glomeruli of glomerulonephritis and in cultured human podocytes under albumin overload. The transcript...
Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and c...
Nephrocalcinosis is a clinicopathological entity characterized by microscopic calcium crystals in the renal parenchyma, within the tubular lumen or in the interstitium. Crystal binding to tubular cells may be the cause underlying nephrocalcinosis and nephrolithiasis. Pathological circumstances, such as acute cortical necrosis, may induce healthy ce...
Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompani...
Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may rep...
Nephrocalcinosis involves the deposition of microscopic crystals in the tubular lumen or interstitium. While the clinical, biochemical and genetic aspects of the diseases causing nephrocalcinosis have been elucidated, little is known about the cellular events in this calcification process. We previously reported a phenomenon involving the spontaneo...
Albumin re-uptake is a receptor-mediated pathway located in renal proximal tubuli. There is increasing evidence of glomerular protein handling by podocytes, but little is known about the mechanism behind this process. In this study, we found that human podocytes in vitro are committed to internalizing albumin through a receptor-mediated mechanism e...
Proteinuria, manifested predominantly as albuminuria, has been recognized as an independent risk
factor for both renal and cardiovascular disease. The loss of proteins is the hallmark of tubular and
glomerular diseases and can be due to structural and/or functional alterations involving different
cell types. Several studies have underlined the invo...
Dent disease (DD) is a rare X-linked recessive renal tubulopathy characterised by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis. DD is caused by mutations in both the CLCN5 and OCRL genes. CLCN5 encodes the electrogenic chloride/proton exchanger ClC-5 which is involved in the tubular reabsorption o...
Pentraxin 3 (PTX3) is an acute-phase protein involved in C1q clearance. The presence of anti-C1q and the absence of anti-PTX3 antibodies were associated with lupus glomerulonephritis (LGLN). Our aim was to assess soluble and kidney-expressed PTX3 and their relationships with anti-C1q and anti-PTX3 antibodies in LGLN. Serum PTX3, anti-C1q, anti-dsDN...
Medullary nephrocalcinosis is a hallmark of medullary sponge kidney (MSK). We had the opportunity to study a spontaneous calcification process in vitro by utilizing the renal cells of a patient with MSK who was heterozygous for the c.-27 + 18G>A variant in the GDNF gene encoding glial cell-derived neurotrophic factor. The cells were obtained by col...
Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease'...
Glomerular protein handling mechanisms have received much attention in studies of nephrotic syndrome. Histopathological findings in renal biopsies from severely proteinuric patients support the likelihood of protein endocytosis by podocytes. ClC-5 is involved in the endocytosis of albumin in the proximal tubule.
Aim
To investigate whether ClC-5 is...
Adjuvants, commonly used in vaccines, may be responsible for inducing autoimmunity and autoimmune diseases, both in humans and mice. The so-called 'ASIA' (Autoimmune/inflammatory Syndrome Induced by Adjuvants) syndrome has been recently described, which is caused by the exposure to a component reproducing the effect of adjuvants. The aim of our stu...
A number of glycosaminoglycan (GAG) species related to heparin, dermatan sulfate (DeS) and chondroitin sulfate were tested
for their ability to interfere with the physiological expression and/or pathological overexpression of the TGF-β1 gene. The
influence of the molecular weight, molecular weight distribution, degree of sulfation and location of t...
Cell turnover in the healthy adult kidney is very slow but the kidney has a strong capacity for regeneration after acute injury. Although many molecular aspects of this process have been clarified, the source of the newly-formed renal epithelial cells is still being debated. Several studies have shown, moreover, that the repair of injured renal epi...
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and is characterized by extremely variable clinical and morphological features and outcome. TGF-beta1 has a key role in fibrogenesis and the progression of renal damage. Its production is under genetic control.
We recruited 105 Italian biopsy-proven IgAN patients for gen...
In kidney transplants, the renin-angiotensin system (RAS) is involved in systemic and local changes that may induce fibrosis. Our aim was to use gene expression and immunohistochemical analysis to investigate the RAS and several factors involved in the fibrogenic cascade in allograft biopsies.
We considered 43 donor biopsies (T0), 18 biopsies obtai...
Randall's plaques are very common in idiopathic calcium-oxalate nephrolithiasis. These papillary plaques have an apatite mineral structure. While these calcium deposits are generally assumed to be secondary to a purely physico-chemical phenomenon, we advance the hypothesis that they form due to a truly ectopic biomineralization in the renal tissue,...
The adult mammalian renal tubular epithelium exists in a relatively quiescent to slowly replicating state, but has great potential for regenerative morphogenesis following severe ischemic or toxic injury. Kidney regeneration and repair occur through three cellular and molecular mechanisms: differentiation of the somatic stem cells, recruitment of c...
List of differentially expressed genes. Genes numbered from 1 to 554 (column A) passed both statistical analyses (SAM and "intensity-dependent calculation of standard Z-score", see Methods), those numbered from 555 to 993 passed only the SAM analysis. The other columns show: (B) the OPERON oligo ID in the OMAD database [50]; (C) the EntrezGene ID;...
KEGG analysis of differentially expressed genes. 267 genes in Additional file 1 with an EntrezGene ID were placed in the KEGG maps using the "color genes" option in the KEGG database [41]. Differentially expressed genes that only passed the SAM analysis were colored orange (up-regulated) and light-blue (down-regulated); genes that passed both stati...
Understanding how mesenchymal cells arise from epithelial cells could have a strong impact in unveiling mechanisms of epithelial cell plasticity underlying kidney regeneration and repair. In primary human tubular epithelial cells (HUTEC) under different TGF beta 1 concentrations we had observed epithelial-to-mesenchymal transition (EMT) but not epi...
The origin and fate of renal interstitial myofibroblasts (MFs), the effector cells of renal fibrosis, are still debated. Experimental evidence suggests that renal MFs derive from tubular epithelial cells throughout the epithelial-mesenchymal transition (EMT) process. Primary human tubular epithelial cells (HUTECs) were cultured for 4 and 6 days on...
Introduction Although the origin of renal interstitial myofibroblasts is still a matter of debate ( Powell et al . 1999 ), emerging evidences suggest that they may derive from tubular epithelial cells. Since the well‐known mesenchymal origin of human tubular epithelial cells (HUTECs), our working hypothesis is that in renal fibrogenesis, fibrogenet...
In a number of experimental models of nephropathy, heparin is renoprotective because it inhibits mesangial matrix synthesis and cell proliferation; in most of these models, glomerular macrophage infiltration has a pathogenic role. We investigated the hypothesis that heparin might also be renoprotective by modulating the macrophages in various ways...
Gene expression can be examined with different techniques including ribonuclease protection assay (RPA), in situ hybridisation (ISH), and quantitative reverse transcription-polymerase chain reaction (RT/PCR). These methods differ considerably in their sensitivity and precision in detecting and quantifying low abundance mRNA. Although there is evide...
Chronic induction of the prosclerotic cytokine transforming growth factor beta (TGF-beta) has been implicated in the pathogenesis of diabetic nephropathy. In a rat model of diabetes mellitus-induced glomerulosclerosis, daily administration of a modified heparin (mH) glycosaminoglycan (GAG) preparation with low anticoagulant activity prevented glome...
It is hypothesized that in acute and chronic CsA nephrotoxicity, in vivo models CsA side-effects are mediated by Renin-Angiotensin II (RAS)-TGF-beta-1 pathway. However, to induce chronic nephrotoxicity, CsA administration has to be combined with a low salt diet, which causes hemodynamic changes and RAS up-regulation.
In order to define any direct c...
The prosclerotic transforming growth factor beta1 (TGF-beta1) is a key factor in the induction and maintenance of fibrosis in different organs. To assess relative changes in TGF-beta1 mRNA levels, the comparative kinetic reverse transcription-polymerase chain reaction strategy was used. In this method, cellular mRNA levels of the target and a house...
At present, it is not clear whether mesangial proliferation underlies mesangial expansion in diabetic nephropathy. To address this issue and the relationship between heparin's renoprotective and antimitogenic activities, we studied three streptozotocin-induced diabetic rat groups 5 and 12 months after diabetes induction: two groups were administere...
Transforming growth factor beta 1 (TGF-beta 1) is a multifunctional regulator of cell-growth, differentiation and extracellular matrix formation in several physiological conditions. It plays a crucial role in the process of glomerulosclerosis. Mature TGF-beta 1 is secreted as a latent form associated with the latency associated peptide (LAP), and i...
Diabetic nephropathy is one of the leading causes of renal failure in Western countries, where diabetic patients account for nearly half of all patients on haemodialysis. Progressive expansion of the mesangial matrix, and thickening of the glomerular and tubular basement membranes without signs of major cell proliferation are hallmarks of human and...
Regulation of mesangial matrix deposition is a dynamic phenomenon involving synthetic and degradative processes. The latter involve a number of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP). Experimental studies suggest that mesangial matrix degradation is inhibited in diabetic nephropathy, and that this...
Transforming growth factor β1 (TGF-β1) is a multifunctional regulator of cell-growth, differentiation and extracellular matrix formation in several physiological conditions. It plays a crucial role in the process of glomerulosclerosis. Mature TGF-β1 is secreted as a latent firm associated with the latency associated peptide (LAP), and its activatio...
Diabetic nephropathy is associated with thickening of the glomerular basement membrane and, in particular, with mesangial matrix expansion. Previous studies have indicated that administration of chemically modified, low-anticoagulant heparins prevents some of the morphologic and physiologic alterations occurring in experimental diabetic nephropathy...
Diabetic nephropathy is characterized by glomerular basement membrane thickening and mesangial expansion. Immunohistochemical studies of diabetic kidneys showed an increased collagen type IV synthesis and deposition in the mesangial matrix, while the glomerular heparan sulfate proteoglycan content was decreased. In nodular glomerulosclerosis massiv...
Glycosaminoglycan administration has favourable effects on morphological and functional renal abnormalities in different models. The possibility that exogenous glycosaminoglycans modulate glomerular matrix synthesis was explored in both primary and SV40-MES13 murine mesangial cell cultures. On both cell types, both low-molecular-weight heparin and...
