Localization and distribution of anionic charges in the glomerular mesangium of normal and nephrotic rats

Sulfated glycosaminoglycans and sialoglycoproteins are thought to play a pivotal role in the glomerular capillary wall barrier to filtration since these anionic charged elements are important in the maintenance of capillary wall integrity and constitute a charge-selective filter. The development of proteinuria in puromycin aminonucleoside (PAN) nephrosis is associated with polyanion loss from the glomerular capillary wall structures. Since in PAN nephrosis the permeability of the mesangial area to plasma proteins and tracer substances has also been shown to be increased, the purpose of this study was to analyse the localization and distribution of anionic charges in the glomerular mesangium in this experimental model. Glycosaminoglycans were labeled by perfusion of the kidneys with ruthenium red solution (RR). Electron microscopic examination revealed the presence of distinct small RR granules ("anionic sites") in the mesangial intercellular matrix substance and in the laminae rarae of the glomerular basement membrane (GBM). The center-to-center spacing of the granules was measured and a frequency distribution of intervals in different interval classes was constructed. In normal glomeruli the anionic sites in the mesangial matrix showed a distribution pattern identical to the GBM with a maximal interval incidence at the 31-40 nm class. In nephrotic rats anionic site distributions in matrix and GBM did not change significantly. Sialoglycoproteins were labeled with colloidal iron (CI). In PAN nephrosis a decrease of CI binding was observed at the epithelial-basement membrane junction of the glomerular capillary wall. However, CI labeling of the mesangial matrix and mesangial cell membranes did not differ from that of normal glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intraglomerular fibronectin in rat experimental glomerulonephritis.

To clarify the mechanisms of glomerular pericapillary fibronectin deposition in human membranous nephropathy and mesangial proliferative glomerulonephritis, intraglomerular fibronectin distribution was examined by light and electron microscopy using the experimental rat models of Heymann and nephrotoxic serum nephritis. As previously demonstrated by immunofluorescence microscopy (Pettersson and Colvin 1978; Ikeya et al. 1985, 1986), fibronectin was distributed in the mesangial areas and occasionally on percicapillary walls of normal glomeruli, while in nephrotoxic serum nephritis and Heymann nephritis, fibronectin was diffusely located along glomerular capillary walls as well as in the mesangium. By immunoelectron microscopy using the immunogold technique, fibronectin was also noted in the mesangial areas and the lamina densa of the glomerular basement membrane (GBM) in normal glomeruli. In nephrotoxic serum nephritis, fibronectin was seen around mesangial cells situated between endothelial cells and the GBM, suggesting that pericapillary fibronectin in nephrotoxic serum nephritis reflects mesangial extension. However, in Heymann nephritis, it was found uniformly in the lamina rara interna, lamina densa and lamina rara externa of the GBM, indicating no specific relation to glomerular cells. When sections of normal and both experimental nephritis kidneys were incubated with fluorescein isothiocyanate conjugated with rat plasma fibronectin, a linear pattern of fluorescein staining along the glomerular capillary walls was observed in Heymann nephritis but not in normal or nephrotoxic serum nephritic rats. The GBM in Heymann nephritis would thus appear to have an affinity for plasma fibronectin. Based on the above findings, fibronectin in the GBM of rats with Heymann nephritis may reasonably be concluded to originate from the plasma.     

Involvement of mesangial cells expressing alpha-smooth muscle actin during restorative glomerular remodeling in Thy-1.1 nephritis.

The function of actin cytoskeleton in mesangial cells (MCs) during the recovering process of injured glomeruli is not fully understood. MCs in injured glomeruli express alpha-smooth muscle actin (alpha-SMA), which is not detected in normal glomeruli. We focused on the localization of alpha-SMA in MCs of Thy-1.1 nephritic rat. Expression of alpha-SMA in the injured glomeruli peaked at day 5 after antibody injection and then declined gradually. At day 5, MCs, where alpha-SMA was localized at their cytoplasmic processes situated in various positions, occupied the expanded mesangium. MCs expressing alpha-SMA tended to be located at the peripheral region close to the glomerular basement membrane (GBM) or endothelial cells at day 8. Localization of alpha-SMA within the peripheral MCs was restricted to the cytoplasmic processes radiating toward the GBM and touching it with their tips at day 8. These alpha-SMA-containing processes are suitable to transmit the contractile force to GBM and may contribute to normalize the expanded glomerular volume. In addition, an actin-binding protein, drebrin, was localized in all MC processes extending toward various directions throughout the course of nephritis, suggesting that drebrin is involved in the formation of MC processes.     

The glomerular mesangium: a comparative study of mesangial handling of iron dextran complex and endogenous IgG in mice and rats

The function and channel system of the glomerular mesangium in mice and rats was investigated by studying the uptake and transport of intravenously injected iron-dextran particles, and the localization of endogenous IgG. Animals were killed at 30 min, 8 h, 1 and 3 days and 1 and 2 weeks after intravenous injection of iron dextran complex. It was found that the tracer was present maximally in the mesangium of the mouse at one day after injection whereas a maximum was not reached until the third day in the rat. Maximal levels of tracer particles in the extra-glomerular lacis area were found at three days in the mouse and at 2 weeks in the rat. Disappearance of the tracer from the blood as indicated by the measured serum iron levels did not seem to differ significantly in the two species. Using an ultrastructural immunoperoxidase technique, considerable amount of endogenous IgG were localized in the mesangial channel system in the stalk region and in the extraglomerular lacis area of mice, whereas in rats only very scanty endogenous IgG was present in these locations. It is suggested that the difference in mesangial handling of macromolecular material in mice and rats is more likely to be due to a different rate of transport through the mesangial channel system than to primary differences in mesangial phagocytotic activity.     

Freeze-fracture cytochemistry of rat glomerular capillary tuft. Determination of wheat germ agglutinin binding sites and localization of anionic charges

We propose here the use of freeze-fracture to gain access and to label in vitro glomerular components and locate WGA receptors and anionic sites. Tissues are frozen, fractured under liquid nitrogen, and thawed. Freeze-fracture rendered all glomerular structures directly accessible to the reagents. This made possible study of the nature and topology of cationized ferritin and WGA binding sites. WGA-gold complexes were observed over plasma membranes of podocytes and of endothelial and mesangial cells. Labeling of podocytes and endothelial cells was similar in the mesangial area and in the peripheral part of the capillary loop. Cross-fractures of extracellular matrices showed that WGA bound uniformly to the glomerular basement membrane (GBM) as well as to mesangial matrix. In fractured specimens treated with neuraminidase, WGA was no longer observed over podocytes but it consistently labeled the surface of endothelial and mesangial cells. Whereas in GBM cross-sections WGA binding was greatly reduced or even abolished, it remained unmodified in the mesangium. This shows that only NeuNAc (sialic acid) might account for the binding of WGA to podocytes, whereas GlcNAcs appear to be the main WGA binding sites on endothelial and mesangial cells and in the mesangial matrix. Both NeuNAc and GLcNAc residues are probably associated in GBM. With cationized ferritin (pI 8.3) at pH 7.4, intense, continuous labeling was seen all over the different plasma membranes, denser in podocytes than in endothelial cells. CF was also observed in cross-fractured profiles of extracellular matrices and never appeared agglutinated in discrete sites.     

Experimental Dirofilaria immitis-associated glomerulonephritis induced in part by in situ formation of immune complexes in the glomerular capillary wall

Eight dogs were immunized with an aqueous-soluble extract of adult Dirofilaria immitis. Subsequent to at least 7-fold increases in antibody titer, the left renal artery of each dog was infused with 6 mg of D. immitis antigen. Fourteen days after infusion, the left kidney was compared to the right kidney and preinfusion biopsies. All dogs developed glomerular lesions in the left kidney characterized by 1 or more of the following: mesangial cell proliferation, neutrophil infiltration, increased periodic acid-Schiff-positive staining of the mesangium and glomerular basement membrane (GBM), fibrin deposition, and thickening of the GBM. Left kidney glomerular immunofluorescence was positive in 7 of the 8 dogs using polyclonal antisera for canine IgG and C3 in a linear or fine granular pattern. Ultrastructural lesions were present in the left kidney of all dogs and consisted of irregular GBM thickening, intramembranous and mesangial electron-dense deposits, and mesangial and endothelial cell proliferation. Antibodies directed against D. immitis antigen were demonstrated in all kidney eluates from the left kidney. The right kidneys of 3 of the dogs developed lesions; however, in comparison to the left kidney, the lesions in the right kidneys were inconsistent, mild, and focal. The histologic findings in the left kidney were similar to those observed in dogs with naturally occurring D. immitis infections. In sham-immunized control dogs, renal arterial infusion of D. immitis antigen did not cause consistent immune complex glomerulonephritis; however, antigen adherence to glomerular capillary walls was observed by immunofluorescent microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental immune complex glomerulonephritis in the mouse with two types of immune complexes.

Immune complex glomerulonephritis was induced in three groups of mice by long-term immunization. Two antigens of similar molecular weight were used. The first group was immunized with ferritin (mol wt 480,000). In altered glomeruli deposits of immune complexes were seen in the subendothelial and subepithelial spaces of the glomerular basement membrane (GBM) and in the mesangium. The immune complex deposits were formed by amorphous matrix with marked dense molecules of ferritin. The second group was immunized with human fibrinogen (mol wt 450,000). The immune complex deposits were present in the intramembranous, subepithelial and subendothelial spaces of the GBM and in the mesangium. These deposits were relatively less electron-dense and had a fine granular structure. The third group of mice were immunized with both ferritin and fibrinogen simultaneously. Two types of deposits situated subendothelially in the GBM and in the mesangium were seen in one animal of this group. One type of deposit resembled structurally the ferritin-antiferritin complex deposits, the other resembled the fibrinogen-antifibrinogen complex deposits. The individual deposits in the GBM and in the mesangium formed discrete homogeneous masses. The two types of deposit were occassionally in direct contact with one another, but were more often completely separate and were never mixed. It can be assumed that in at least some phase of the experiment both types of complex were present in the circulating blood simultaneously. However, since none of the complexes deposited in the GBM or in the mesangium were mixed, it seems probable that each type of complex is deposited separately in the form of "clusters" composed of a single type of complex. The phagocytic activity of mesangial cells of animals with complex glomerulonephritis was not increased when compared with control animals.     

Rat mesangial cell-matrix interactions in culture

The glomerular mesangium contains fibronectin (FN), laminin, and collagen IV, but it remains unclear whether these matrix proteins affect mesangial cellular functions. The present experiments were designed to test whether cell-matrix interactions could affect some functions of mesangial cells. Cultured rat mesangial cells synthesized a cellular form of FN that was both secreted and incorporated into an extensive, fibrillar pericellular matrix. This FN matrix was increased in high-density cultures and was more developed in human mesangial cells. Rat mesangial cells in vitro displayed a marked capacity to incorporate exogenous FN into a pericellular matrix, demonstrating that accumulations of FN in the mesangial matrix could result from endogenous and/or exogenous sources. Rat mesangial cells also expressed RGD-sensitive integrin receptors for FN, laminin, and collagens I and IV that promoted cell adhesion and that directed differential changes in morphology. Indirect evidence suggested the existence of other mesangial binding sites for extracellular matrix proteins. FN and collagen IV also stimulated modest increases in [3H]thymidine uptake and cell number by quiescent cells. Taken together, these results suggest that cultured mesangial cells present a model system for studying the regulation of cell-matrix interactions in the mesangium.     

Pathogenic role of TGF-β in the progression of podocyte diseases

In patients with progressive podocyte diseases, such as focal segmental glomerulosclerosis and membranous nephropathy, there is enhanced expression of transforming growth factor (TGF-β) in podocytes. Biomechanical strain in these diseases may cause overexpression of TGF-β and angiotensin II (Ang II) by podocytes. Oxidative stress induced by Ang II may activate the latent TGF-β. Increased TGF-β activity by podocytes may induce not only the thickening of the glomerular basement membrane (GBM), but also podocyte apoptosis and/or detachment from the GBM, initiating the development of glomerulosclerosis. Furthermore, mesangial matrix expansion frequently occurs in podocyte diseases in association with the development of glomerulosclerosis. This review examines open questions on the pathogenic role of TGF-β that links podocyte injury to GBM thickening, podocyte loss, mesangial matrix expansion and glomerulosclerosis in podocyte diseases. It also describes paracrine regulatory mechanisms of podocyte TGF-β on mesangial cells leading to increased matrix synthesis.     

Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane

In developing glomeruli, laminin alpha5 replaces laminin alpha1 in the glomerular basement membrane (GBM) at the capillary loop stage, a transition required for glomerulogenesis. To investigate domain-specific functions of laminin alpha5 during glomerulogenesis, we produced transgenic mice that express a chimeric laminin composed of laminin alpha5 domains VI through I fused to the human laminin alpha1 globular (G) domain, designated Mr51. Transgene-derived protein accumulated in many basement membranes, including the developing GBM. When bred onto the Lama5 -/- background, Mr51 supported GBM formation, preventing the breakdown that normally occurs in Lama5 -/- glomeruli. In addition, podocytes exhibited their typical arrangement in a single cell layer epithelium adjacent to the GBM, but convolution of glomerular capillaries did not occur. Instead, capillaries were distended and exhibited a ballooned appearance, a phenotype similar to that observed in the total absence of mesangial cells. However, here the phenotype could be attributed to the lack of mesangial cell adhesion to the GBM, suggesting that the G domain of laminin alpha5 is essential for this adhesion. Analysis of an additional chimeric transgene allowed us to narrow the region of the alpha5 G domain essential for mesangial cell adhesion to alpha5LG3-5. Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha5. Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the GBM.     

Paracrine role for TGF-β-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease

Transforming growth factor-β (TGF-β) is a key regulator of extracellular matrix (ECM), and may mediate the development of glomerulosclerosis with accumulation of mesangial matrix. Mesangial cells secrete TGF-β in response to common in vitro fibrogenic stimuli. Yet mesangial immunostaining for active TGF-β1 is frequently negative in chronic glomerular disease. TGF-β is rather expressed and/or activated by podocytes in both mesangial and podocyte diseases. Activated TGF-β/Smad signaling by podocytes may induce connective tissue growth factor (CTGF or CCN2) and vascular endothelial growth factor (VEGF) expression. Podocyte CTGF seems to have paracrine effects on mesangial cells to stimulate CTGF expression. CTGF appears to stimulate the fibronectin-matrix assembly via enhanced cell-surface expression of α5β1 integrin in the mesangium of diseased glomeruli. Podocyte VEGF-A overexpression also seems to play a paracrine role on mesangial cells to upregulate VEGF/VEGF receptor systems and to overproduce matrix proteins. Thus, paracrine CTGF and VEGF may contribute to mesangial matrix accumulation in chronic glomerular disease, culminating in the development of glomerulosclerosis. Together, these data bring new mechanistic insights into our understanding of the pathogenic role of TGF-β-induced CTGF and VEGF in mesangial matrix expansion in chronic progressive glomerular disease.     

Glomerular extracellular matrices in rat diabetic glomerulopathy by scanning electron microscopy

Characteristic pathological changes in the glomeruli in diabetic nephropathy include expansion of the mesangial matrix and thickening of the glomerular basement membrane (GBM). Using an acellular digestion technique combined with scanning electron microscopy, the three-dimensional ultrastructural changes in glomerular extracellular matrices were studied in rats with diabetic glomerulopathy. Diabetes was induced by the intravenous injection of streptozotocin and morphological analyses were performed 3, 6 and 11 months after the injection. Expansion of mesangial area and GBM thickening became evident with time. After treatment with the series of detergents, all cellular components were completely removed leaving the extracellular matrices intact. In normal controls, the mesangial matrix appeared as fenestrated septa with oval or round stomata between the glomerular capillaries. In diabetic glomerulopathy, expansion of mesangial matrix and narrowing of the mesangial fenestrae were observed. These changes in the mesangial matrices seem to play a vital role in the progression of glomerulosclerosis in rat diabetes. A subendothelial thin layer of the GBM was continuous with the mesangial matrix. One cause of GBM thickening in streptozotocin diabetes may be expansion of the mesangial matrix into the peripheral GBM.     

Glomerular extracellular matrices and anionic sites in aging ddY mice: a morphometric study

A morphometric study was undertaken to examine age-related changes in glomerular ultrastructure and anionic sites in ddY male mice at various ages. A progressive increase in glomerular extracellular matrices, including thickening of the glomerular basement membrane (GBM), formation of GBM nodules, and mesangial matrix increase, was found to be the primary age-related ultrastructural change in aging mice; there were also electron-dense deposits in mesangial and subepithelial regions. The extent of GBM thickening in mice was less than was reported in rats. Rather, the GBM nodules, which had the same electron density as the lamina densa (LD) and protruded on the subepithelial side of the GBM, were more striking. Quantitative evaluation showed that GBM thickness, number and size of GBM nodules, and the area of the mesangial matrix were significantly correlated with the age of the mice. The distribution of anionic sites in the glomeruli of aging animals was described for the first time. No statistically significant differences were noted between the number of glomerular anionic sites in the different age groups. These results indicate that the increase in glomerular extracellular matrices reported in aged rats was also present in aged mice, although the extent of various changes was different. The results also indicate that this increase in glomerular extracellular matrices with age was not accompanied by significant alteration in glomerular anionic sites.     

Loss of laminin epitopes during glomerular basement membrane assembly in developing mouse kidneys.

Kidney glomerular basement membranes (GMBs) originate in development from fusion of a dual basement membrane between endothelial cells and primitive epithelial podocytes. After fusion, segments of newly synthesized matrix, derived primarily from podocytes, appear as subepithelial outpockets and are spliced into GBMs during glomerular capillary loop expansion. To investigate GBM assembly further, we examined newborn mouse kidneys with monoclonal rat anti-mouse laminin IgGs (MAb) conjugated to horseradish peroxidase (HRP). In adults, these MAb strongly label glomerular mesangial matrices but bind only weakly or not at all to mature GBMs. In contrast, anti-laminin MAb intensely bound newborn mouse GBMs undergoing initial assembly. After intraperitoneal injection of MAb-HRP into neonates, dense binding occurred across both subendothelial and subepithelial pre-fusion GMBs as well as forming mesangial matrices. Considerably less MAb binding was seen, however, in post-fusion GBMs from more mature glomeruli in the same section, although mesangial matrices remained positive. In addition, new subepithelial segments in areas of splicing were negative. These results conflict with those obtained previously with injections of polyclonal anti-laminin IgGs into newborns or adults, which result in complete labeling of all GBMs. Although epitope masking cannot be completely excluded, we believe that decreased MAb binding to developing GBM reflects actual epitope loss. This loss could occur by laminin isoform substitution, conformational change, and/or proteolytic processing during GBM assembly.     

Molecular basis of IgA nephropathy

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and remains an important cause of end-stage renal failure. However, the basic molecular mechanism(s) underlying abnormal IgA synthesis, selective mesangial deposition with ensuing mesangial cell proliferation and extracellular matrix expansion remains poorly understood. Notably, the severity of tubulointerstitial lesions better predicts the renal progression than the degree of glomerular lesions. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. This review will summarize the earlier works on the structure of the IgA molecule, mechanisms of mesangial IgA deposition and pathophysiologic effects of IgA on mesangial cells following mesangial deposition. Recently, a series of important advances in the area of communication between the glomerular mesangium and renal tubular cells have emerged. These novel findings regarding the molecular pathogenesis of IgAN will be helpful in designing future directions for therapy.     

Distribution of sulfated glycosaminoglycans in the glomerular basement membrane and mesangial matrix

The relative distribution of heparan sulfate-glycosaminoglycan (HS-GAG) and chondroitin sulfate-glycosaminoglycans (CS-GAG) of the mesangial matrix (MM) and the glomerular basement membrane (GBM), which represent the two glomerular extracellular matrices, was determined by a combination of enzymatic treatments and autoradiographic methods. The kidneys were digested in situ either with heparinase (degrades HS and CS-GAG) or chondroitinase-ABC (degrades CS-GAG). Subsequently, the sulfated GAGs were labeled with a radioiodinated analog of cationic ferritin (CF, pI approximately 7.5). The tissues were then processed for light and electron microscopic autoradiography. The autoradiographic analysis showed that sulfated GAGs are distributed both in the GBM and mesangial matrix. The predominant GAG present in both the matrices is HS-GAG and the CS-GAG is exclusively present in the mesangial matrix. These data indicate that the GBM and mesangial matrix are compositionally different. These differences may be of importance in the establishment of normal glomerular function and organization and in the alteration of that function and organization as a result of various disease processes, especially of those that are immune-complex mediated.     

Glomerular Deposition of Properdin in Henoch-Sch?nlein Syndrome and Idiopathic Focal Nephritis

Biopsy of renal tissue from four patients with idiopathic focal nephritis and three patients with Henoch-Schönlein syndrome showed that C3 and properdin were deposited with IgA in the glomerular mesangium, C1q could not be detected. These observations suggest that glomerular injury in disorders characterized by mesangial deposits of IgA and C3 is mediated via the properdin system.     

Differential expression of type IV collagen isoforms in rat glomerular endothelial and mesangial cells

Type IV collagen, which is encoded by six genetically distinct alpha-chains (alpha 1-alpha 6), is a major component of the kidney glomerulus. The alpha 1(IV) and alpha 2(IV) chains are present predominantly in the mesangial matrix, whereas the alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains are localized almost exclusively to the glomerular basement membrane (GBM). Thickening of the GBM and expansion of the mesangial matrix are believed to contribute to the pathogenesis of diabetic nephropathy. In the present study, we evaluated the expression of alpha 1(IV), alpha 3(IV), and alpha 5(IV) chains in rat glomerular endothelial (GEndC) and mesangial cells (GMC). Under physiological concentrations of glucose (5 mM), alpha 1(IV) and alpha 5(IV) chains were detectable in GMCs, with an obvious absence of alpha 3(IV) chain. All three isoforms tested were present in GEndCs. At diabetic concentrations of glucose (25 mM), alpha 1(IV) was up-regulated in GMCs, whereas expression level of alpha 1(IV) remained unaltered in GEndCs. The alpha 3(IV) and alpha 5(IV) chains were up-regulated in GEndCs, but remained unchanged in GMCs under diabetic glucose concentrations (25 mM). Collectively, our results demonstrate that GMC might contribute to mesangial matrix expansion, mediated by alpha 1(IV) collagen, while GEndC might contribute to thickening of GBM, mediated by alpha 3(IV) collagen, in patients with diabetic nephropathy.     

Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling

We recently modeled fluid flow through gap junction channels coupling the pigmented and nonpigmented layers of the ciliary body. The model suggested the channels could transport the secretion of aqueous humor, but flow would be driven by hydrostatic pressure rather than osmosis. The pressure required to drive fluid through a single layer of gap junctions might be just a few mmHg and difficult to measure. In the lens, however, there is a circulation of Na(+) that may be coupled to intracellular fluid flow. Based on this hypothesis, the fluid would cross hundreds of layers of gap junctions, and this might require a large hydrostatic gradient. Therefore, we measured hydrostatic pressure as a function of distance from the center of the lens using an intracellular microelectrode-based pressure-sensing system. In wild-type mouse lenses, intracellular pressure varied from ～330 mmHg at the center to zero at the surface. We have several knockout/knock-in mouse models with differing levels of expression of gap junction channels coupling lens fiber cells. Intracellular hydrostatic pressure in lenses from these mouse models varied inversely with the number of channels. When the lens' circulation of Na(+) was either blocked or reduced, intracellular hydrostatic pressure in central fiber cells was either eliminated or reduced proportionally. These data are consistent with our hypotheses: fluid circulates through the lens; the intracellular leg of fluid circulation is through gap junction channels and is driven by hydrostatic pressure; and the fluid flow is generated by membrane transport of sodium.     

Pathophysiological Roles of Gap Junction in Glomerular Mesangial Cells

Glomerular mesangial cells (MCs) are specialized vascular smooth muscle cells that play a critical role in the control of glomerular hemodynamics. One of the intriguing features of MCs is their extraordinary abundance in gap junctions (GJs). It has long been speculated that GJs may bridge MCs together and provide the mesangium with the characteristics of a functional syncytium. Accumulating scientific evidence supports this idea. GJs are reported to be critically involved in important physiological processes like tubuloglomerular feedback and glomerular filtration. In addition, GJs are implicated in the control of many cellular processes of MCs, including growth, differentiation and survival. This article summarizes the current knowledge on the roles of GJs in glomerular pathophysiology.