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The podocyte is a highly specialized cell that plays a key role in regulating the glomerular filtration barrier. A number of advances have been made in recent years, linked to the discovery of single-gene defects in hereditary glomerular disease, which highlight the role of this cell in preventing proteinuria. This article reviews the molecular biology of the podocyte, focusing on known genetic abnormalities.
The cause of proteinuria in renal disease is the subject of intensive research and, latterly, the podocyte, a specialized epithelial cell of the kidney glomerulus, has been the focus of much of this endeavour. It is a complex cell with functions and structural features that have an important role in the development of proteinuria. This review explores some of the characteristics of the podocyte and how abnormalities of its structure and function may have particular relevance to the development and progression of clinical diabetic nephropathy.
Type 2 diabetes mellitus has reached epidemic proportions and diabetic nephropathy is the leading cause of end-stage renal disease. The metabolic syndrome constitutes a milieu conducive to tissue redox stress. This loss of redox homeostasis contributes to renal remodeling and parallels the concurrent increased vascular redox stress associated with the cardiometabolic syndrome. The multiple metabolic toxicities, redox stress and endothelial dysfunction combine to weave the complicated mosaic fabric of diabetic glomerulosclerosis and diabetic nephropathy. A better understanding may provide both the clinician and researcher tools to unravel this complicated disease process. Cellular remodeling of podocyte foot processes in the Ren-2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27) and the Zucker diabetic fatty model of type 2 diabetes mellitus have been observed in preliminary studies. Importantly, angiotensin II receptor blockers have been shown to abrogate these ultrastructural changes in the foot processes of the podocyte in preliminary studies. An integrated, global risk reduction, approach in therapy addressing the multiple metabolic abnormalities combined with attempts to reach therapeutic goals at an earlier stage could have a profound effect on the development and progressive nature to end-stage renal disease and ultimately renal replacement therapy.
We have recently found in male homozygous hypertensive Ren-2 transgenic rats (TGRs) fed a high-salt diet that early onset selective endothelin (ET) A (ET(A)) or nonselective ET(A)/ET B (ET(B)) receptor blockade improved survival rate and reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy, whereas selective ET(A) receptor blockade also significantly attenuated the rise in blood pressure. Because antihypertensive therapy in general is known to be more efficient when started at early age, our study was performed to determine whether onset of ET receptor blockade at a later age in animals with established hypertension will have similar protective effects as does early-onset therapy. Male homozygous TGRs and age-matched normotensive Hannover Sprague-Dawley rats were fed a high-salt diet between days 51 and 90 of age. TGRs received vehicle (untreated), the selective ET(A) receptor blocker atrasentan (ABT-627), or the nonselective ET(A)/ET(B) receptor blocker bosentan. Survival rates in untreated and bosentan-treated TGRs were 50% and 64%, respectively, whereas with atrasentan, survival rate of TGR was 96%, thus, similar to 93% in Hannover Sprague-Dawley rats. From day 60 on, systolic blood pressure in atrasentan-treated TGRs was transiently lower (P<0.05) than in untreated or bosentan-treated TGRs. Glomerular podocyte injury was substantially reduced with atrasentan treatment independent of severe hypertension and strongly correlated with survival (P<0.001). Our data indicate that in homozygous TGR ET receptors play an important role also in established hypertension. Selective ET(A) receptor blockade not only reduces podocyte injury and end-organ damage but also improves growth and survival independently of hypertension.
Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-1alpha (HIF-1alpha), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4alpha and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4alpha, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1alpha protein expression was partially attenuated by pioglitazone. These results suggest that not only metabolic alteration and oxidative stress, but also the alteration of gene expression related to glomerulogenesis and podocyte structure, may be involved in the pathogenesis of early diabetic glomerulopathy in type 2 diabetes.
The ultrastructural organization of the cytoskeleton of normal podocytes and glomerular endothelial cells was studied in man (adults and children) and in adult Sprague-Dawley rats. In podocytes of both species, cytoplasmic microtubules (MT) were observed in the cell body close to the Golgi apparatus and along the main axis of the major processes where they formed bundles. A network of intermediate filaments (IF) was observed in the cell body and in the major processes where they sometimes formed bundles parallel to MT, especially in man. Numerous clustered microfilaments (MF) were noticed in the foot processes close to the plasma membrane. In glomerular endothelial cells from both species, networks of MT and IF were observed in the cell body, whereas MF surrounded the endothelial fenestrations. The high degree of organization of the cytoskeleton suggests that it may play an important role in several functions of both cell types.
The concept that the podocyte is the major culprit underlying development and progression of glomerular diseases leading to chronic renal failure is well established. The essential steps in this process are (1) the establishment of tuft adhesions to Bowman's capsule; (2) the formation by capillaries contained in a tuft adhesion of a filtrate that is delivered, instead into Bowman's space, towards the interstitium; and (3) the spreading of this filtrate on the outer aspect of the affected nephron leading to the degeneration of this nephron. The present review summarizes the pros and cons concerning the relevance of misdirected filtration for a nephron-to-nephron transfer of the disease at the level of the tubular interstitium. Surprisingly, the histopathology clearly shows that interstitial proliferation surrounding degenerating nephrons tends to encapsulate the degenerative process, confining it to the already affected nephron. No evidence is available that the disease, mediated by interstitial proliferation and matrix deposition, may jump to a neighboring, so far unaffected, nephron. It appears that the process that leads to the degeneration of a nephron in the context of "classic" FSGS always starts separately in the respective glomerulus by severe podocyte injury.
In several metasomal blood vessels of Phoronis muelleri myofilament-containing podocytes are the predominatnt cell-type. In some regions the podocytes can build a labyrinth resembling e.g. the glomerular epithelium of Enteropneusta and the axial organ of Asteroidea.
The progressive renal disease model of chronic uninephrectomy-desoxycorticosterone-trimethylacetate (UNX-DOCA) hypertension is associated with mesangial proliferation as a major disease mechanism. A detailed structural analysis of the alterations in glomerular structure which accompany the development of sclerosis in this model has not been made. Male Munich-Wistar rats underwent UNX, received weekly injections of the aldosterone agonist DOCA and 1% sodium chloride as drinking solution and were compared with sham operated controls (CON). Thirty eight days after onset, UNX animals had an albuminuria of 183 +/- 180 mg/day versus 0.38 +/- 0.22 mg/day in CON. Kidneys were fixed by total body perfusion and renal tissue processed for light and electron-microscopy. Superficial and deep total glomerular volume increased from 2.18 +/- 0.15 (deep: 2.57 +/- 0.24) 10(6) microns 3 in CON to 3.98 +/- 0.81 (deep: 3.95 +/- 0.63) 10(6) microns 3 in UNX. In addition to overall tuft hypertrophy, structural analysis revealed severe destruction of tuft architecture with mesangial expansion and/or capillary ballooning, leading to local tuft enlargements. Podocytes overlying the expanded areas appeared unable to adapt to cover the increased tuft surfaces. They developed severe lesions in cell architecture leading to denudation of glomerular basement membrane (GBM)-areas. "Naked" GBM appears to represent a nidus for hyalinosis, thrombosis and synechia formation, which progresses to segmental sclerosis. In the UNX-DOCA model of chronic glomerular hypertension local mesangial expansion was frequently encountered but no evidence was found that mesangial proliferation and matrix production proceeded to sclerosis. The crucial damage to the glomerulus in this model would appear to be attributable to podocyte failure, with the resultant GBM denudation triggering synechia formation, hyalinosis and ultimately glomerulosclerosis.
A metaplastic transformation of the parietal layer of the Bowman's capsule into podocytes is described in glomerular cysts induced by postnatal injection of methylprednisolone acetate to rabbits. Both the anomalous location of podocytes and their utility for the study of the biology of the cells are discussed.
Nephrotoxic serum nephritis was produced in rats by intraperitoneal injections of rabbit nephrotoxic serum. Heterologous and autologous phases of nephritis were demonstrated by immunofluorescence and ultrastructural studies. Scanning electron microscopy showed changes in the surface of the podocytes, swelling of the arm-like cytoplasmic processes, and disappearance of the pedicles. The podocyte alterations are discussed.
AIMS/HYPOTHESIS: The predictive value of glomerular structure on progression of renal disease was examined in patients with Type II (non-insulin-dependent) diabetes and microalbuminuria (urinary albumin-to-creatinine ratio = 30-299 mg/g). METHODS: Kidney biopsy specimens were obtained from 16 diabetic Pima Indians (6 men, 10 women). Progression of renal disease was assessed by measuring urinary albumin excretion 4 years after the biopsy (UAE(4 years)) and by computing the change in urinary albumin excretion during the study (Delta UAE). RESULTS: At baseline, the duration of diabetes averaged 13.3 years (range = 4.0-23.8 years) and the mean glomerular filtration rate was 159 ml x min(-1) x 1.73 m(-2) (range = 98 - 239 ml x min(-1) x 1.73 m(-2)). Median urinary albumin excretion was 67 mg/g (range = 25-136 mg/g) and it increased to 625 mg/g (range = 9-13471 mg/g) after 4 years; 10 subjects (63 %; 4 men, 6 women) developed macroalbuminuria (urinary albumin-to-creatinine ratio >/= 300 mg/g). Neither mean arterial pressure nor HbA(1 c) changed substantially during follow-up. Among the glomerular morphologic characteristics, the number of visceral epithelial cells, or podocytes, per glomerulus was the strongest predictor of renal disease progression (UAE(4 years), r = -0.49, p = 0.05; DeltaUAE, r = -0.57, p = 0.02), with fewer cells predicting more rapid progression. Glomerular basement membrane thickness did not predict progression (UAE(4 years), r = 0.11, p = 0.67; DeltaUAE, r = 0.09, p = 0.73) and mesangial volume fraction had only a modest effect (UAE(4 years,) r = 0.42, p = 0.11; DeltaUAE, r = 0.48, p = 0.06). CONCLUSION/INTERPRETATION: Whether lower epithelial cell number per glomerulus among those that progressed was due to cellular destruction, a reduced complement of epithelial cells, or both is uncertain. Nevertheless, these findings suggest that podocytes play an important part in the development and progression of diabetic renal disease. [Diabetologia (1999) 42: 1341-1344]
The decline in renal function in chronic renal failure is based on the progressive loss of viable nephrons. The pathways to nephron loss in conjunction with chronic renal disease generally start in the glomerulus, extending onto the tubulointerstitium via the urinary pole. Pathways to nephron degeneration starting focally in the tubulointerstitium have yet to be described. The deleterious effects of protein leakage on progression appear to be a result of podocyte damage, the beneficial effects of ACE inhibitors a result of podocyte protection.
Galloway-Mowat syndrome is an autosomal recessive disorder characterized by early onset nephrotic syndrome and central nervous system anomalies. Mutations in podocyte proteins, such as nephrin, alpha-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. The genetic defect in Galloway-Mowat syndrome is as yet unknown. We postulated that in Galloway-Mowat syndrome the mutation would be in a protein that is expressed both in podocytes and neurons, such as synaptopodin, GLEPP1, or nephrin. We therefore analyzed kidney tissue from normal children (n=3), children with congenital nephrotic syndrome of the Finnish type (CNF, n=3), minimal change disease (MCD, n=3), focal segmental glomerulosclerosis (FSGS, n=3), and Galloway-Mowat syndrome (n=4) by immunohistochemistry for expression of synaptopodin, GLEPP1, intracellular domain of nephrin (nephrin-I), and extracellular domain of nephrin (nephrin-E). Synaptopodin, GLEPP1, and nephrin were strongly expressed in normal kidney tissue. Nephrin was absent, and synaptopodin and GLEPP1 expression were decreased in CNF. The expression of all three proteins was reduced in MCD and FSGS; the decrease in expression being more marked in FSGS. Synaptopodin, GLEPP1, and nephrin expression was present, although reduced in Galloway-Mowat syndrome. We conclude that the reduced expression of synaptopodin, GLEPP1, and nephrin in Galloway- Mowat syndrome is a secondary phenomenon related to the proteinuria, and hence synaptopodin, GLEPP1, and nephrin are probably not the proteins mutated in Galloway-Mowat syndrome.
Decrease of anionic sites and heparan sulfate proteoglycan has been demonstrated in diabetic glomerular basement membrane (GBM) and causally related to albuminuria. The HID-TCH-SP-PD technique is a sensitive histochemical method for negatively charged sulfated carbohydrates. In this study, we examined the localization of HID-TCH-SP-PD reaction in the glomeruli of diabetic and control rats. In both rats, the reaction was found in association with the surface of podocytes and with GBM. In diabetic rats, the former-associated reaction was markedly reduced. By contrast, the latter-associated reaction did not show any differences between both animal groups. Urinary albumin excretion (UAE) increased significantly in alloxanized rats. It is suggested that a decrease of podocyte-associated sulfated carbohydrates, the primary observed change, gives rise to albuminuria in alloxan diabetic rats.
Molecular mechanisms governing the loss of glomerular membrane perm selectivity during progression of proteinuric kidney diseases are so far poorly defined. Discovery of the proteins of the podocyte slit diaphragm, including the nephrin-CD2AP-podocin complex, has represented a major breakthrough in understanding the crucial role of the glomerular epithelial layer in the pathogenesis of proteinuria in human congenital disorders. A number of studies have tried to address the role of nephrin in acquired proteinuric disorders with conflicting results. In human diabetic nephropathy a defect of nephrin gene and protein expression has been consistently reported, which translates in profound changes of filtration slit ultrastructural architecture. The exclusive effect of angiotensin II inhibitors of restoring deficient nephrin expression in proteinuric diseases underlines a close interaction between angiotensin II and podocyte proteins and indicates a fresh way to look at the renoprotective properties of these molecules.
We investigated the distribution of nephrin by immunofluorescence microscopy in renal biopsies of patients with nephrotic syndrome: 13 with membranous glomerulonephritis (GN), 10 with minimal change GN, and seven with focal segmental glomerulosclerosis. As control, six patients with IgA GN without nephrotic syndrome and 10 normal controls were studied. We found an extensive loss of staining for nephrin and a shift from a podocyte-staining pattern to a granular pattern in patients with nephrotic syndrome, irrespective of the primary disease. In membranous GN, nephrin was co-localized with IgG immune deposits. In the attempt to explain these results, we investigated in vitro whether stimuli acting on the cell cytoskeleton, known to be involved in the pathogenesis of GN, may induce redistribution of nephrin on the surface of human cultured podocytes. Aggregated but not disaggregated human IgG(4), plasmalemmal insertion of membrane attack complex of complement, tumor necrosis factor-alpha, and puromycin, induced the shedding of nephrin with a loss of surface expression. This phenomenon was abrogated by cytochalasin and sodium azide. These results suggest that the activation of cell cytoskeleton may modify surface expression of nephrin allowing a dislocation from plasma membrane to an extracellular site.
Rats with a nephrotoxic serum nephritis reveal changes of proteinuria and content of serum proteins as well as serum cholesterol in the direction of a nephrotic syndrome as is seen after Daunomycin. Nevertheless, the morphological findings with TEM and especially with SEM are quite different. A striking feature of the nephritis is the rather good preservation of cell processes through all the time of experiment in spite of the elevated proteinuria. Moreover, podocytes with furrowed or ribbed surfaces originate and are most numerous when the signs of inflammation are most pronounced. These furrowed podocytes are interpreted as representing a special reactive, perhaps mobilized form. With SEM it is evident that the glomeruli are altered focally and segmentally in the nephrotoxic serum nephritis.