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PubMedDate not supplied

Blood glucose and lipid control as risk factors in the progression of renal damage in type 2 diabetes.

One of the central functions of the kidney is to excrete low molecular weight, water soluble, plasma, waste products into the urine, whereas macromolecules, the size of albumin and larger, are retained. The flow of the glomerular filtrate is thought to follow an extracellular route, passing through the endothelial fenestrae, then across the glomerular basement membrane and finally through the slit diaphragm between the foot processes of podocytes. Recently it has been hypothesized that microalbuminuria leading to proteinuria and to end stage renal disease (ESRD) is mainly due to an altered glomerular fitration barrier at podocyte level. The "conditio sine qua non" for the development of diabetic ESRD is hyperglycemia. However, arterial hypertension and abnormalities of blood lipid concentrations and structure are also an important antecedent of such complication in diabetes mellitus. Interestingly it has been suggested that hyperglycemia, arterial hypertension and dyslipidemia cause disorderes of albumin excretion rate by damaging podocyte and slit diaphragm protein scaffold with over production of and extracellular release of oxygen radical species at glomerular level. The present review will briefly discuss recent reports which describe the relationship between blood glucose and lipid abnormalities and the occurrence and progression of renal damage in diabetes mellitus. More particularly we will give evidence that the risk of a rapid decline of glomerular function abruptly increases when glycated hemoglobin is steadily higher than 7.5% and postprandial blood glucose is above 200 mg/dL. Eventually we will analyze recent reports showing that treatment with statins, the inhibitors of hydroxymethylglutaryl-coenzyme A reductase, ameliorate the course of renal function in type 2 diabetic patients. It is not yet fully understood whether this effect is due to the lowering of the circulating levels of low density lipoproteins (LDL) or to an improved endothelial function or to lower patterns of LDL oxidation.

Blood Glucose↗

PubMed1992

Investigation of glomerular lesions in dogs with acute experimentally induced Ehrlichia canis infection.

Six male Beagles were inoculated with Ehrlichia canis. Transient proteinuria was confirmed during the acute phase of infection by serial determination of urinary protein-to-creatinine ratio. Peak urine protein loss, consisting principally of albumin, was observed 2.5 to 3.5 weeks after inoculation. Renal biopsy specimens were obtained before inoculation, during peak proteinuria, and 10 weeks after inoculation when proteinuria had resolved. Renal tissue was evaluated by use of light, immunofluorescent, and electron microscopy to correlate specific glomerular lesions with development of proteinuria. Histologic examination revealed perivenular and interstitial infiltrates of lymphocytes and plasma cells localized principally to the renal cortex. Glomerular lesions were minimal to absent. Immunofluorescent staining revealed moderate to marked deposition of anti-canine IgG and IgM in the glomerular tufts and mesangium. Depositions of anti-canine complement factor C3 were not observed. Immunofluorescent staining persisted 10 weeks after inoculation, despite resolution of proteinuria, and probably represented passive trapping of immunoglobulins. Ultrastructural examination revealed fusion of podocyte processes that coincided with development of proteinuria. Electron-dense deposits or changes in the basement membrane were not observed. Morphometric measurements of average podocyte process length and percentage of coverage of basement membrane by podocyte processes were used to quantify the degree of process fusion. Both measurements increased significantly (P < 0.05) during peak proteinuria, and returned to preinoculation values when proteinuria had resolved 10 weeks after E canis inoculation. These findings indicated possible minimal-change glomerulopathy, rather than immune-complex glomerulonephritis, during acute E canis infection and could explain transient proteinuria without histologic evidence of glomerular disease.

Animals↗

PubMed2004

The morphological characteristics and expression of cell cycle regulatory proteins in cellular variants of idiopathic focal segmental glomerulosclerosis.

OBJECTIVE: To investigate the morphological characteristics and expression of cell cycle regulatory proteins in cellular variants of idiopathic focal segmental glomerulosclerosis (FSGS). METHODS: Seventeen cases of cellular variants of FSGS were studied by light microscopy, immunofluorescence (IF), and electron microscopy (EM). The immunohistochemistry and immunoelectron microscopy for the detection of cyclins (cyclin D1, cyclin E, cyclin A, cyclin B1) and cyclin dependent kinase inhibitors (CKIs, including p21, p27, p57) were performed in these cases. RESULTS: The hypertrophy and hyperplasia of epithelial cells overlying sclerotic or collapsed glomerular tufts were the prominent characteristics of cellular variants of FSGS; IF showed segmental deposits of IgM; hyperplastic epithelial cells possessed the features of both podocyte and parietal epithelial cells ultrastructurally. Hyperplastic epithelial cells of cellular lesions showed positive staining for cyclin E, cyclin A, cyclin B1 and p21, and negative staining for cyclin D1, p27 and p57. CONCLUSION: The hyperplastic epithelial cells in cellular variants of FSGS may be derived from damaged podocytes, which mimic the immature podocytes, re-engage the cell cycle to proliferate and form the cellular lesions. The up-regulation of cyclins (cyclin E, cyclin A, cyclin B1) concurrent with the loss of CKIs (p27, p57) contributes to the cell cycle regulation of cellular lesions of FSGS.

Adolescent↗

PubMed2004

[Focal segmental glomerulosclerosis].

Focal segmental glomerulosclerosis (FSGS) is one of the major causes of nephrotic syndrome in adult as well as in the children. Untreated or steroid-resistant primary FSGS often shows a progressive renal insufficiency and reaches to end-stage renal failure. Concerning the treatment for such patients, the combined immunosuppressive therapy with corticosteroid and other cytotoxic drugs (cyclophosphamide, cyclosporine and tacrolimus etc.) is recommended. Since podocyte injury seems to be the most important primary events in FSGS, the extensive studies have been focused on the role of podocyte-related molecules. Recently slit membrane-associated molecules (CD2AP, alpha-actinin 4 and podocin) and angiotensin II type I receptor in the podocyte have been clearly shown to be relevant for the pathogenesis of FSGS.

Actinin↗

PubMed2005

[Structure and function of the glomerular filtration barrier].

The aim of the review is to discuss recent investigations on the glomerular filtration barrier. The barrier consists of three layers: the vascular endothelium, the glomerular basement membrane and the slit diaphragm located between podocyte foot processes. The main components of the slit diaphragm are nephrin, the product of NPHS1 gene and podocin, the product of NPHS2 gene. Mutations in NPHS1 lead to congenital nephrotic syndrome of the Finnish type (CNF), whereas NPHS2 mutations result in focal segmental glomerulosclerosis (FSGS). In both cases massive proteinuria is accompanied by the effacement of podocyte foot processess. Reduced expression and redistribution of nephrin and podocin are also seen in podocytes of patients with acquired glomerulopathies. The results suggest that those proteins play a pivotal role in the processes responsible for glomerular filtration. Together with podocin and CD2AP (CD2-associated protein), nephrin forms a complex determining the integrity of the slit diaphragm. Its function has not yet been fully understood and the pathways of signal transduction need to be elucidated.

Adaptor Proteins, Signal Transducing↗

PubMed2004

[Idiopathic collapsing glomerulopathy in children: report of two cases].

OBJECTIVE: Idiopathic collapsing glomerulopathy (ICG) is a clinically and pathologically distinct variant of focal segmental glomerulosclerosis, which is characterized by proteinuria (often nephrotic range) and rapid progression to end-stage renal failure. The typical pathological changes are global/segmental glomerular collapse, hypertrophy and hyperplasia of podocytes and severe tubulointerstitial lesions. Most ICG patients who have been reported in previous published papers are adults. ICG in children is rare. The study aimed to analyze and investigate clinical manifestations, renal histopathological findings, treatment and outcomes of ICG in children. METHODS: Data of two cases of ICG, a 7-year-old boy and a 12-year-old girl, were analyzed. Both of them were Chinese and Han. Clinical characteristics, results of laboratory tests, renal histopathological findings, treatment, outcomes and prognosis of the two children with ICG were retrospectively analyzed. Results were compared with published data. RESULTS: These two children presented typical clinical features of nephrotic syndrome. The quantity of 24 hr urine protein was 7.6 g/d (0.47 g/kg x d for boy) and 10.67 g/d (0.35 g/kg x d for girl). Both of them had hypertension (blood pressure ranged from 130/90 to 150/110 mmHg) and hypercholesterolemia (15.4 mmol/L for the boy and 11.3 mmol/L for the girl). The serum albumin was 12 g/L for girl and 23 g/L for boy. The creatinine clearance rate gradually decreased from normal range to 30 ml/min for the girl. The histopathological changes in renal biopsy of them were focal segmental or global glomerular collapse, hypertrophy and hyperplasia of podocytes and severe tubulointerstitial lesions. These two cases were steroid-resistant and were treated with pulse intravenous methylprednisolone and pulse intravenous cyclphosphamade in one case, who rapidly progressed to end-stage renal failure and died half a year later. Another one was treated with cyclosporine. He showed continuous hypertention and heavy proteinuria for eight months. CONCLUSION: ICG in the 2 children was a severe disease which presented steroid-resistant nephrotic syndrome and rapidly progressive renal failure. The pathological characteristics was global/segmental glomerular collapse, hypertrophy and hyperplasia of podocytes and severe tubulointerstitial lesions. In children with ICG treatment was difficult and the prognosis was poor.

Child↗

PubMed1990

Ultrastructure of the nephron of grey mullets (Mugil cephalus L. and Liza saliens Risso 1810).

Mugil cephalus and Liza saliens nephrons consist of renal corpuscles, neck segments, first, second and third proximal segments, collecting segments and collecting ducts. The glomerular endothelial cells are fenestrated showing a thin diaphragm. Mesangial cells are located around and between the capillaries, suggesting a role in vessel contraction; they show no phagocytic ultrastructural features. An extensive part of the podocyte surface lies flat on the glomerular basement membrane; this characteristic is probably related to the diminishing of the glomerular filtration rate. Podocytes show large multivesicular bodies, lysosomes and vesicles with a dense bar. Large globules in the podocytes point to their possible secretory activity. The first proximal segment is made up of principal cells with a well developed brush border and tightly packed basal infoldings, and scarce ciliated cells. The second proximal segment consists of principal cells, with loose-packed microvilli and numerous deep basal invaginations, ciliated cells and dark cells. The third proximal segment shows cells with irregularly arranged microvilli and a basal labyrinth, and some ciliated cell. The collecting segment and the collecting duct cells were characterized by apical mucous droplets; the latter also show a well developed basal labyrinth and are surrounded by a layer of smooth muscle cells.

Animals↗

PubMed1987

Scanning electron microscopy of cellular and acellular glomeruli of male dogs affected with Samoyed hereditary glomerulopathy and a carrier female.

Glomeruli isolated from three male dogs affected with Samoyed hereditary glomerulopathy were compared by scanning electron microscopy with glomeruli of one carrier female and six unaffected dogs. Scanning electron microscopy was performed before and after removal of podocytes and endothelial cells with enzyme and detergent, producing cellular and acellular glomeruli respectively. Cellular glomeruli of unaffected dogs showed podocytes with normally arranged foot processes, while in acellular glomeruli, the subepithelial surface of glomerular capillary basement membranes appeared smooth to finely granular. In contrast, cellular glomeruli of affected males showed microvilli, globular cytoplasmic projections from podocytes, and effacement of foot processes; acellular glomeruli demonstrated ridges and plaque-like irregularities on the subepithelial surface of glomerular capillary basement membranes. Changes in the glomeruli of the carrier female were intermediate between those of unaffected and affected male dogs. The appearance of the subepithelial surface of glomerular capillary basement membranes of acellular glomeruli seen by scanning electron microscopy correlated with the extent of multilaminar splitting of glomerular capillary basement membranes seen by transmission electron microscopy.

Animals↗

PubMed1985

Studies with monoclonal antibodies against brush border antigens in Heymann nephritis.

The authors have prepared and studied three murine monoclonal antibodies that are reactive with antigens in brush border regions of proximal renal tubules of rats. Two of the antibodies, 14C1 and AG3, were derived from mice immunized with Fx1A and the third, 4H6, from a mouse immunized with isolated glomeruli obtained from rats with Heymann nephritis. Immunohistochemical, immunoelectron microscopic, and immunochemical studies showed that the three antibodies recognized different antigens. The antibody 14C1 recognized the previously described nephritogenic glycoprotein, gp 330, in microvillar brush border preparations, and reacted with material present on podocyte cell surfaces of normal rat kidneys, especially in coated pits, as well as with material in the glomerular deposits of rats with Heymann nephritis. The antibody 4H6 recognized a 110-kilodalton microvillar antigen and reacted with material in the glycocalyx of podocytes of normal glomeruli, but showed only equivocal reactivity with material in the deposits in Heymann nephritis. AG3 failed to immunoprecipitate a distinctive antigen in microvillar preparations and did not react with the glomeruli of normal rats or of rats with Heymann nephritis. All three antibodies reacted with epithelial cells in the intestine, epididymis, and placenta; 4H6 also reacted with thin loops of Henle as well as with endothelial cells or other cells in lung, lymphoid tissue, liver, and spleen. The results demonstrate that not all brush border antigens participate in Heymann nephritis and confirm that an antigen (gp 330) involved in the formation of glomerular deposits in Heymann nephritis is normally present on podocyte surfaces, especially in coated pits, but is not present in extracellular sites.

Animals↗

PubMed1979

[Morphological changes in the kidneys during nonspecific ulcerative colitis].

Light microscopy, immunohistochemical examinations and electron microscopy of kidney biopsies showed the different localization of immune complexes in the glomeruli (subepithelial, intramembraneous, subendothelial, and mesangial immune complexes) and various forms of materialization of their harmful effect (induction of immune inflammation or immunosuppression) to be determined by the involvement in phagocytosis and reparation reactions of either podocytes or mesangial and endothelial cells and also hematogenous elements. Therefore, podocyte, mesangioendothelial and podocyte-mesangioendothelial ways of morphogenesis of immunocoplex glomerulonephritis may be distinguished. Each of them is associated with the development of certain clinico-morphological forms of immunocomplex glomerulonephritis which should be considered as distinct entities.

Adolescent↗

PubMed1984

Glomerular epithelial cell changes after ischemia or dehydration. Possible role of angiotensin II.

Glomerular visceral epithelial cells (podocytes) undergo flattening and spreading of major processes detectable by scanning electron microscopy in early postischemic acute renal failure in both animals and man. The authors examined the kinetics of development of these epithelial cell changes in the renal pedicle-clamping model of ischemic renal failure in the rabbit. They found that these changes develop progressively, increasing with increasing length of ischemia, and occur while the pedicle clamp is still in place. To assess the possible role of angiotensin II and vasopressin in producing the epithelial changes, the authors compared glomerular morphology before and during pedicle clamping in hydrated rabbits and in dehydrated rabbits. Dehydration alone produced changes in glomerular epithelial cells comparable to those seen in the postischemic kidney. The angiotensin-converting enzyme inhibitor captopril did not prevent the podocyte changes in either group. In vitro incubation studies confirmed that both angiotensin II and vasopressin produce glomerular epithelial cell changes with a threshold between 10(-7) M and 10(-8) M, a concentration that may be physiologically significant for angiotensin II, which is synthesized at the glomerulus and may have local paracrine effects. Such local synthesis may not be inhibited by systemic administration of captopril. Angiotensin II may play a role in producing podocyte alterations during renal ischemia, as well as in the dehydrated state.

Angiotensin II↗

PubMed1982

Distribution of intramembrane particles and filipin-sterol complexes in plasma membranes of kidney. I. Corpuscle of Malpighi.

A quantitative study was performed on glomerular cell types from the rat kidney freeze fractured after conventional fixation or following exposure to the sterol-specific antibiotic, filipin. The results reveal a considerable variation on the size and number of intramembrane particles, as well as in the number of filipin-sterol complexes present on plasma membranes of the different cell types present in the glomerulus. These differences in membrane structure probably reflect specialized functions of the individual plasma membranes within the glomerulus. The most striking observation, however, was the low particle content and poor filipin labeling of podocyte foot process bases (which lie against the basal lamina) compared with the rest of the podocyte plasma membrane. The presence of distinct membrane domains in podocytes may be a factor involved in maintaining their specific architecture that is critical for the normal functioning of the kidney filtration barrier.

Animals↗

PubMed1982

Chronic Masugi nephritis in the rat. An electron microscopic study on evolution and consequences of glomerular capsular adhesions.

Chronic focal glomerulonephritis was induced in the rat by using goat nephrotoxic IgG. In the later stage (6 to 15 months) a number of glomeruli were found to be attached to Bowman's capsule with variable segmental sclerosis and/or hyalinosis. The morphogenesis of the changes was studied by electron microscopy. It was found that partial cytoplasmic necrosis of podocytes was an initiating event of the capsular adhesion. When this occurred in the peripheral tufts, the denuded portion of the glomerular basement membrane (GBM) became attached to the parietal epithelium, resulting in progressive thickening of the mesangium and GBM, deposition of hyaline or proteinaceous material, and desquamation of the endothelial sheet, the features being compatible with segmental glomerular sclerosis and/or hyalinosis. It seemed that these changes, in turn, accelerated podocyte desquamation and extension of the capsular adhesion, producing a progressive cycle that terminated in global glomerular hyalinosis. Such a sequence of events most often occurred in rats with massive proteinuria, suggesting that persistent, severe proteinuria caused the podocyte lesion which led to the development of segmental glomerular sclerosis and/or hyalinosis.

Animals↗

PubMed1993

Ethanol effect on the ionic transfer through isolated human amnion. II. Cellular targets of the in vitro acute ethanol action and of the antagonism between magnesium, taurine and ethanol.

The ultrastructure of the human amniotic membrane from normal pregnancies at term, was studied by transmission electron microscopy. The results were analysed by a stereological method which indicates the ratio between the area of intercellular spaces (R1), microvilli (R2) and podocytes (R3) versus the cell area. Addition of ethanol (0.4 g/l) in the external medium decreased R1 and R3 and had no significant effect on R2. Ethanol reduced intercellular space and podocyte exchange surface. Two mM MgCl2 or 2 mM taurine restored R1 and R3 to normal values. The cellular targets of the antagonism between Mg, taurine and ethanol are particularly intercellular spaces and podocytes.

Amnion↗

PubMed1996

Adult, fetal, and polycystic kidney expression of polycystin, the polycystic kidney disease-1 gene product.

The polycystic kidney disease-1 gene, which is mutated in the majority of patients with autosomal dominant polycystic kidney disease, has been identified. The protein encoded by this gene, polycystin, has no homology with any gene known thus far. To gain more insight into the function of polycystin, we raised antibodies against synthetic peptides and a fusion protein corresponding to the sequence of two different fragments of polycystin. Two of the antibodies were capable of immunoprecipitating an in vitro transcription and translation product corresponding to a fragment of polycystin. In the cyst-lining epithelium of polycystic kidney disease-1 patients, a strong staining was observed. In normal adult and embryonic kidney tissues, expression was seen in the epithelium of all tubular structures and in the glomerular parietal and visceral epithelium (podocytes), although the podocytes were mainly recognized on cryosections and not on paraffin sections. A double-labeled immunofluorescence with one of the polycystin antibodies and the monoclonal antibody 8G8 ascertained that within the glomerular tuft podocytes were recognized.

Adult↗

PubMed1996

Sialic acid expression in normal and diseased human kidney.

Three sialic acid-specific lectins, Tritrichomonas mobilensis (TML) (without linkage preference), Maackia amurensis leukoagglutinin (MAL) (alpha2,3) and Sambucus nigra agglutinin (alpha2,6 linkage-specific), were used for detection of sialylated glycoconjugates in normal and diseased human kidneys. Normal kidneys demonstrated strong podocyte positivity of alpha2,3 linked sialic acid and weaker sialic acid expression on capillary endothelium, which was alpha2,6 linked. Renal biopsies (45) representing a variety of diseases, e.g. minimal change disease, membranous, membranoproliferative glomerulonephritis, tubulointerstitial nephrosis or diabetic glomerulopathy showed increased sialic acid expression in glomerular capillaries, Bowman's capsule epithelium and on podocytes. In several different kidney diseases the glomerular endothelium expressed also alpha2,3 linked sialic acid along with increased TML-positivity of epithelial cells related to alpha2,6 linked sialic acid. No difference in sialic acid linkage expression was observed in the tubules, which expressed putative alpha2,6 linked sialic acid on the luminal surface of cells distal to the descending limb of Henle's loop. The study did not show changes characteristic of specific diseases. Rather, increased sialic acid expression on glomerular endothelium and podocytes was linked to a variety of pathological changes. It is assumed that changes in sialysation of glycoconjugates in the glomeruli represent nonspecific changes and do not reflect fundamental pathogenetic features of renal diseases.

Galactose↗

PubMed1997

Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis.

Puromycin aminonucleoside nephrosis (PAN), a rat model of human minimal change nephropathy, is characterized by extensive flattening of glomerular epithelial cell (podocyte) foot processes and by severe proteinuria. For comparison of expression of glomerular membrane proteins of normal and PAN rats, a membrane protein fraction of isolated rat glomeruli was prepared and monoclonal antibodies were raised against it. An IgG-secreting clone designated LF3 was selected that specifically immunolabeled podocytes of normal but not of PAN rats. The antigen of LF3 IgG was identified as a 43-kd glycoprotein. Molecular cloning of its cDNA was performed in a delta gt11 expression library prepared from mRNA of isolated rat glomeruli. The predicted amino acid sequence indicated a 166-amino-acid integral membrane protein with a single membrane-spanning domain, two potential phosphorylation sites in its short cytoplasmic tail, and six potential O-glycosylation sites in the large ectodomain. High amino acid sequence identities were found to membrane glycoproteins of rat lung and bone and mouse thymus epithelial cells as well as to a phorbol-ester-induced protein in a mouse osteoblast cell line and to a canine influenza C virus receptor. In PAN, expression of this 43-kd protein was selectively reduced to < 30%, as determined by quantitative immunogold electron microscopy, immunoblotting, and Northern blotting. These data provide evidence that transcription of the 43-kd transmembrane podocyte glycoprotein is specifically down-regulated in PAN. To indicate that this protein could be associated with transformation of arborized foot processes to flat feet (Latin, pes planus) we have called it podoplanin.

Amino Acid Sequence↗

PubMed1998

Ultrastructural changes of the filtration barrier during mouse nephron development.

The development of mouse renal corpuscles localized in the juxtamedullary zone of renal cortex was assessed with the aid of light and electron microscopy. The observations have confirmed the existence of four developmental phases of the nephron. The analysis of filtration barrier components has shown that during the development of the kidney the height of maturing podocytes becomes markedly reduced, and that adherence and occluding junctions formed between them shift from their apices towards their bases. Ladder-like junctions have also been observed between podocytes. The number of their foot processes steadily grows, they become narrower and filtration slit diaphragms begin appear between them. Fusion of podocytes basement membranes and endotheliocytes leads to formation of a doubly thick filtration membrane. As the tuft of the capillary glomerulus grows, newly formed fragments of the basement membrane in the form of loops and pouches start to be evident in its close neighborhood. Large endotheliocytes become greatly flattened and numerous fenestrae appear in their cytoplasm.

Animals↗