Glomerular expression of connexin 40 and connexin 43 in rat experimental glomerulonephritis.

BACKGROUND: Gap junctional intercellular communication is thought to play an important role in the maintenance of cell differentiation and homeostasis. Gap junctions connect glomerular mesangial cells to each other. In this study, we examined the glomerular expression of connexins (Cxs) 40 and 43 at both the protein and transcript levels in anti-Thy1.1 glomerulonephritis (GN). METHODS: Anti-Thy1.1 GN was induced by intravenous injection of anti-Thy1.1 monoclonal antibody 1-22-3. Cx protein expression was examined by immunofluorescence, immunoelectron microscopy, and Western blotting. Changes in mRNA levels were detected by real-time reverse transcriptase-polymerase chain reaction. RESULTS: Cx40 was detected in mesangial cells in normal rat glomeruli; its expression was reduced on days 3 and 7 and recovered to normal on day 14 following GN induction. Cx43 was detected in mesangial cells and podocytes in normal rat glomeruli, and its expression did not change during the disease course of GN. Expression of Cx40 and Cx43 was also detected in extraglomerular mesangial cells; this expression did not change during the disease course. Opposing patterns of expression between Cx40 and smooth muscle actin (SMA) were observed with double-immunofluorescence labeling. SMA is a differentiation marker of mesangial cells; it is often expressed during proliferation but not under physiological conditions. CONCLUSION: These results suggest that Cx40 expression in mesangial cells is related to mesangial cell regeneration. Thus, Cx expression regulation could be a therapeutic target for glomerular diseases.

Angiotensin receptor blockade attenuates glomerulosclerosis progression by promoting VEGF expression and bone marrow-derived cells recruitment.

BACKGROUND: Previous studies have demonstrated that angiotensin Type I receptor blockade (ARB) reduces proteinuria, reverses glomerular injury and glomerulosclerosis in rat models of diabetic nephropathy and glomerulonephritis. However, the cellular and molecular mechanisms are unclear. To investigate the role of cells of the bone marrow (BM) in glomerular repair seen during ARB administration, we induced progressive glomerulosclerosis in enhanced green fluorescent protein BM chimeric rats by a single injection of anti-Thy 1.1 monoclonal antibody, followed by unilateral nephrectomy. METHODS: Cohorts of rats received valsartan or no treatment from Week 2 to Week 8 after induction of disease. Renal function, urinary protein excretion and histological changes were examined 8 weeks after anti-Thy-1.1 monoclonal antibody injection. RESULTS: Valsartan administration improved renal function, reduced severity of glomerulosclrosis and markedly reduced mortality. Valsartan administration promoted regeneration of the glomerular tuft, lowered proteinuria and resulted in enhanced vascular endothelial growth factor (VEGF) expression in the cortex and glomerular tuft. In addition, valsartan promoted increased recruitment of BM-derived cells (BMDCs) many of which expressed VEGF and likely contributed directly to glomerular repair. Nearly all BMDCs recruited to the glomerulus expressed the monocyte/macrophage marker CD68. CONCLUSIONS: In conclusion, the data shows that ARB by valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair which is associated with the recruitment of VEGF producing 'reparative' monocytes and macrophages from the BM.

The effect of renal administration of a selective cyclooxygenase-2 inhibitor or stable prostaglandin I2 analog on the progression of sclerotic glomerulonephritis in rats.

BACKGROUND AND METHODS: There is increasing evidence that a change in glomerular hemodynamics may promote the development of glomerulosclerosis. In this study, we focused on the pharmacological effects of 2 contrasting agents, etodolac, a preferential cyclooxygenase-2 inhibitor, and beraprost sodium (BPS), a prostaglandin I(2) analog, delivered renally, on the disease course of progressive anti-Thy-1 (ATS) glomerulonephritis. RESULTS: Intravital microscopic analysis showed that the diameters of glomerular capillaries and glomerular blood flow in unilaterally nephrectomized (Nx) rats treated locally with BPS were significantly increased, as compared to those of Nx rats treated locally with normal saline (NS) or etodolac. We then examined the effects of BPS and etodolac on the course of progressive glomerulosclerosis. Mesangial cell proliferation, adhesion of glomerular capillary tufts and crescent formation in the BPS-treated group appeared to be more severe compared to the ATS + NS and the ATS + etodolac groups. Scoring of mesangial proliferation and glomerulosclerosis revealed that local BPS treatment significantly worsened glomerular pathology. At day 28, there were significant differences in blood flow between the ATS + etodolac group and both the ATS + NS and ATS + BPS groups, indicating that local treatment with etodolac enhanced the recovery of glomerular circulation. CONCLUSION: This study provides hemodynamic-based evidence showing that disturbance of intraglomerular microcirculation is a critical marker for progressive glomerulonephritis.

Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis.

BACKGROUND: Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN. METHODS: Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system. RESULTS: Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS + aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels. CONCLUSION: This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.

Effects of connexin-mimetic peptides on perfusion pressure in response to phenylephrine in isolated, perfused rat kidneys.

BACKGROUND: Gap junction intercellular communication plays a fundamental role in various tissues and organs. Gap junctions transfer ions and molecules between adjacent cells and are formed by connexins (Cx). It is supposed that vascular conducted responses, which most likely spread through gap junctions in vascular beds, regulate microcirculatory blood flow and maintain vascular resistance. This study provides functional evidence supporting the critical role of gap junctions in a physiological setting and in phenylephrine (PE)-induced vasoconstriction using an ex vivo kidney perfusion technique. METHODS: Using the isolated, perfused kidney model, infusion of gap junction inhibitors and PE, we examined the local effect of gap junction communication. Additionally, gap junction proteins Cx37, Cx40 and Cx43 were detected by immunofluorescence. RESULTS: First, changes in the perfusion pressure were analyzed by infusing the nonselective gap junction uncoupler, 18α-glycyrrhetinic acid (18α-GA), and specific connexin-mimetic peptide inhibitors, (37,43)Gap27, (40)Gap27 and (43)Gap26. Administration of 18α-GA and (43)Gap26 significantly elevated perfusion pressure while infusion of (40)Gap27 and (37,43)Gap27 had no effect. Second, we examined the effect of infusing gap junction inhibitors on PE-induced vasoconstriction. Infusion of 18α-GA and (40)Gap27 significantly suppressed the increase in perfusion pressure induced by PE, while (43)Gap26 and (37,43)Gap27 had no effect. Third, we confirmed by immunofluorescence that Cx37, Cx40 and Cx43 were found in the endothelial cells of interstitial microvessels and that Cx40 was localized in glomerular mesangial cells as well as in smooth muscle cells of the juxtaglomerular area. CONCLUSIONS: This study showed that Cx43 plays a pivotal role in regulating renal vascular resistance and that Cx40 attenuates PE-induced vasoconstriction. These results provide new evidence that gap junctions may control renal circulation and vascular responses.

Exploring the mechanisms of renoprotection against progressive glomerulosclerosis.

In this review, I introduce the strategy developed by our laboratory to explore the mechanisms of renoprotection against progressive glomerulosclerosis leading to renal death. First, I describe the experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis. Second, I discuss the possible mechanisms determining the progression of glomerulosclerosis and introduce a new imaging system based on intravital confocal laser scanning microscopy. Third, I provide an in-depth review of the regulatory glomerular hemodynamics at the cellular and molecular levels while focusing on the pivotal role of Ca(2+)-dependent gap junctional intercellular communication in coordinating the behavior of mesangial cells. Last, I show that local delivery of renoprotective agents, in combination with diagnostic imaging of the renal microvasculature, allows the evaluation of the therapeutic effects of angiotensin II receptor and cyclooxygenase activity local blockade on the progression of glomerulosclerosis, which would otherwise lead to renal death.

Local delivery of angiotensin II receptor blockers into the kidney passively attenuates inflammatory reactions during the early phases of streptozotocin-induced diabetic nephropathy through inhibition of calpain activity.

BACKGROUND/AIMS: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. METHODS AND RESULTS: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-kappaB, as shown by an increase in the expression of the p65 subunit of NF-kappaB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. CONCLUSION: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.

PaO2 greater than 300 mmHg promotes an inflammatory response during extracorporeal circulation in a rat extracorporeal membrane oxygenation model.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is being increasingly used for mechanical support of respiratory and cardio-circulatory failure. An excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. We hypothesized that hyperoxia condition encourages the systemic inflammatory response and organ disorder during ECMO. To prove this hypothesis correct, we investigated the systemic inflammatory responses at normal and high levels of arterial oxygen pressure (PaO2) in the rat ECMO model. METHODS: Rats were randomly assigned to one of the following groups depending on the value of PaO2 during ECMO: A group (n=11, PaO2 100-199 mmHg), B group (n=10, PaO2 200-299 mmHg), C group (n=8, PaO2 300-399 mmHg), and D group (n=11, PaO2 >400 mmHg). Serum cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10)] were measured before, 60, and 120 min after the initiation of ECMO. The wet-to-dry weight (W/D) ratio of the left lung was also measured, and dihydroethidium (DHE) staining, reflecting superoxide generation, of lung and liver tissues was performed 120 min after ECMO initiation. RESULTS: In the C and D groups, the pro-inflammatory cytokines (TNF-α and IL-6) significantly increased during ECMO compared with the other groups. On the other hand, the increase in anti-inflammatory cytokines (IL-10) was more suppressed in the C and D groups than in the other groups. The W/D ratio increased significantly more in the C and D groups than in the other groups. In addition, DHE fluorescence had a tendency to increase as the PaO2 rose. CONCLUSIONS: These data demonstrate that it is better to avoid administration of too much oxygen during ECMO to attenuate lung injury linked to generation of superoxide and the systemic inflammatory response.

The apparition macrophage and Döderlein bacillus is negatively correlated in class I Papanicolaou smear: A morphological examination.

BACKGROUND: Nonspecific vaginitis, also known as Bacterial vaginosis, unlike genital candidiasis and trichomoniasis, is caused by microbiome breakdown. Döderlein's bacillus are gram-positive bacillus that form a microbiome, reproduce in the female vagina after gaining sexual maturity, secrete lactic acid, and prevent the growth of other vaginitis-causing bacteria. Clue cell are squamous epithelial cells with Gardnerella sp. attached to their cell surface. The presence of clue cell is one of the diagnostic criteria for nonspecific vaginitis. Additionally, although macrophages are reported to protect against candidal vaginitis, there are no reports of studies examining the association between macrophages and clue cell. MATERIALS AND METHODS: After re-staining 300 class I specimens by cervical cancer screening with Papanicolaou staining, the appearance of Döderlein's bacillus, macrophages, and clue cell was observed. RESULT: Age group and appearance of Döderlein's bacillus were negatively correlated. The rate of appearance of macrophages was positively correlated with the age group. In people aged 50 years or more, the appearance rate of clue cells was significantly lower in the macrophage appearance group than that in the non-appearance group. CONCLUSION: This study suggested that macrophages, and not Döderlein's bacillus, may play an important role in defense against nonspecific vaginitis.

Disturbances of glomerular hemodynamics: a risk factor determing progression of glomerular diseases?

In this review, we introduce first our experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis. Secondly, we demonstrate a pivotal role for gap-junctional intercellular communication and adenosine triphosphate-dependent intercellular communication, via Ca++ signaling, in coordinating behavior of mesangial and juxtaglomerular cells. This has deepened our understanding of regulatory glomerular hemodynamics at the cellular and molecular levels. Thirdly, we show that local delivery of renoprotective agents such as angiotensin II receptor blockers, in combination with a diagnostic imaging system of the renal microvasculature, allowed us to evaluate the therapeutic effects of local blockade of renin-angiotensin system activity on the progression of glomerulosclerosis, finally leading to renal death.

Alterations of cell adhesion molecules in human glomerular endothelial cells in response to nephritis-associated plasminogen receptor.

BACKGROUND: Acute post-streptococcal glomerulonephritis (APSGN) is induced by glomerular deposition of nephritogenic streptococcal antigen-antibody complexes. Recently, a streptococcal antigen, nephritis-associated plasminogen receptor (NAPlr) was purified from ruptured streptococcal cell supernatants (RCS). However, the cellular and molecular mechanisms of NAPlr action on the glomerular vas culature are still unknown. METHODS: Expression of cell adhesion molecules were measured by cellular ELISA (enzyme-linked immunosorbent assay), immunofluorescence microscopy and Western blot analysis. RESULTS: RCS and NAPlr significantly decreased the PECAM-1 expression in human glomerular endothelial cells (HGECs) as compared to that in the control cells. Plasminogen treatment reversed the RCS or NAPlr-induced decrease of PECAM-1 expression and increase of MCP-1 expression. Immunofluorescent microscopy and Western blot analysis also showed that PECAM-1 expression in HGECs was downregulated upon treatment with RCS or NAPlr and this effect was reversed by plasminogen treatment. Furthermore, we found that tumor necrosis factor-alpha production in culture medium of HGECs was increased at the lower level when the culture system was treated with RCS. CONCLUSION: RCS and NAPlr modulated PECAM-1 expression and MCP-1 production in HGECs, indicating the involvement of NAPlr in inflammatory cell accumulation in glomerular tufts and functional abnormality of glomerular microvasculature such as hyperpermeability.

ATP-dependent mechanism for coordination of intercellular Ca2+ signaling and renin secretion in rat juxtaglomerular cells.

A change in intracellular Ca2+ is considered to be the common final signaling pathway through which renin secretion is governed. Therefore, information relating to the generation, control, and processing of Ca2+ signaling in juxtaglomerular cells (JG) will be critical for understanding JG cell behavior. In this study, we investigated the means by which JG cells harmonize their intracellular Ca2+ signals and explored the potential role of these mechanisms in renin secretion. Mechanical stimulation of a single JG cell initiated propagation of an intercellular Ca2+ wave to up to 11.9+/-4.1 surrounding cells, and this was prevented in the presence of the ATP-degrading enzyme, apyrase (1.7+/-0.7 cells), or by desensitization of purinergic receptors via pretreatment of cells with ATP (1.8+/-0.9 cells), thus implicating ATP as a mediator responsible for the propagation of intercellular Ca2+ signaling. Consistent with this, JG cells were demonstrated not to express the gap junction protein connexin43, and neither did they possess functional gap junction communication. Furthermore, massive mechanical stretching of JG cells elicited a 3-fold increase in ATP release. Administration of ATP into isolated perfused rat kidneys induced a rapid, potent, and persistent inhibition of renin secretion, together with a transient elevation of renal vascular resistance. ATP (1 mmol/L) caused up to 79% reduction of the renin secretion activated by lowering the renal perfusion flow (P<0.01). Taken together, our results indicate that under mechanical stimulation, ATP functions as a paracellular mediator to regulate renin secretion, possibly through modulating intra- and intercellular Ca2+ signals.

Establishment of immortalized human glomerular endothelial cell lines and their application.

BACKGROUND: The experimental use of cultured endothelial cells derived from the microvasculature such as glomerular endothelial cells possesses many problems, including limited growth rates, heterogeneity and loss of specific cell properties dependent on culture passage. In this study, we attempted to establish immortalized, human glomerular endothelial cell (HGEC) lines. METHODS: HGECs of up to 5 passages were transformed by infection with simian virus (SV)-40. After 4-6 weeks the surviving, foci-forming cells were harvested and cloned. Each cell line obtained was examined by immunofluorescence with antibodies to antigens specific for vascular endothelial cells. The expression of adhesion molecules on cells incubated with or without TNF-alpha was also examined by cellular ELISA. RESULTS: Three of twelve cell lines obtained expressed SV40 large T-antigen and von Willebrand's factor, as well as endothelial cell adhesion molecules including ICAM-1 (CD54), PECAM-1 (CD31) and E-selectin (CD62E). In these cells, ICAM-1 and E-selectin expression was up-regulated by TNF-alpha, as in native cultured HGEC. CONCLUSIONS: These cell lines maintain the morphologic and functional characteristics of HGEC even after 60 passages. Immortalized HGEC will be useful for research on glomerular cell biology and provide a standardized substrate for anti-endothelial cell antibody detection.

Establishment of a novel enzyme-linked immunosorbent assay for Thy-1; quantitative assessment of neuronal degeneration.

In the central nervous system (CNS), Thy-1 is expressed predominantly on neurons and serves as a specific marker for neurons. In the present study, we established a two-site enzyme-linked immunosorbent assay (ELISA) that detects trace amounts of Thy-1 protein. Recombinant Thy-1 protein expressed in Escherichia coli was purified and used as a standard. Of the regions of the nervous system examined, the highest Thy-1 concentration was found in the striatum followed by the hippocampus, neocortex, cerebellum, spinal cord, retina and optic nerve. We found that injection of a neurotoxin, N-methyl-D-aspartate, into the vitreous cavity reduced the Thy-1 level in the retina. Thy-1 ELISA will be useful for quantitative assessment of neurodegeneration in the CNS.

Effect of high glucose on nitric oxide production and endothelial nitric oxide synthase protein expression in human glomerular endothelial cells.

BACKGROUND: Hyperglycemia directly contributes to the development of diabetic nephropathy. Nitric oxide (NO), a potent endothelium-derived vasodilator, has been suggested to participate in the regulation of renal blood flow, glomerular filtration rate, and mesangial matrix accumulation. Human vascular endothelial cells are known to exhibit functional heterogeneity, this prompted us to do the first study of NO bioavailability in human glomerular endothelial cells (HGECs), in response to high glucose exposure. METHODS: NO release was examined by detecting nitrite generation by the Griess assay in HGECs exposed to control-level (5.5 mM) and high-level (15, 30 and 60 mM) glucose solutions at various time periods (24, 48 and 72 h) in the presence or absence of L-arginine (1 mM), or superoxide dismutase (SOD) (250 U/ml). In addition, we evaluated the effect of glucose on the expression of endothelial nitric oxide synthase (eNOS) in HGECs by Western blotting. RESULTS: Final levels of nitrite generated in HGECs were reduced significantly, in a time- and concentration-dependent manner, after high glucose exposure. However, Western blot analysis revealed that eNOS protein expression was significantly upregulated at 12 h after exposure to high glucose concentrations (30 mM), reaching a peak at 48 h (twofold increase over baseline levels). The inhibitory effect of high glucose on NO production was restored by the addition of SOD. Addition of L-arginine (1 mM) to external media also reversed the inhibitory effect of high glucose on NO production of HGECs as well. CONCLUSIONS: The present study demonstrated that high glucose increased eNOS protein expression, but decreased NO release finally. Decreased NO bioavailability seems to be associated with overproduction of superoxide and L-arginine deficiency. These findings provide an important clue in clarifying the molecular basis of the mechanisms by which elevated glucose leads to an imbalance between NO and superoxide, resulting in impaired endothelial function. In addition, restoration of NO function by both administration of L-arginine and adequate intake of antioxidants suggests a potential supportive treatment for patients with diabetic nephropathy.

Changes in renal vessels following the long-term administration of an angiotensin II receptor blocker in Zucker fatty rats.

INTRODUCTION: The nephro-protective effects of angiotensin II receptor blockers (ARBs) are widely known; however, there are few reports of long-term effects focusing on the renal vessels. We studied afferent arteriolar changes induced by the long-term administration of an ARB. MATERIALS AND METHODS: Thirty-two 6-week-old male Zucker fatty rats (ZFRs) were divided into following four groups (n = 8 in each): ZFR Group and ZFR+High Group fed a standard or high-salt diet, respectively; ZFR+ARB Group and ZFR+High+ARB Group fed a standard or high-salt diet with ARB (Olmesartan, 5 mg/kg/day), respectively. Blood pressure, proteinuria, morphological examinations and glomerular haemodynamics in vivo were studied. RESULTS: Marked proliferative changes in the afferent arteriolar smooth muscle cells (SMCs) were frequently observed in the two groups given ARBs; in the ZFR+ARB group (77.3±10.3%) compared with the two groups without ARB (1.7%, p < 0.005; 1.2%, p < 0.0005) and 37.4±15.6% in the ZFR+High+ARB group. Proteinuria markedly decreased in the groups treated with ARBs, but the glomerular erythrocyte velocities showed no differences. CONCLUSIONS: Our findings indicate that long-term ARB administration induced unusual proliferative changes in SMCs of afferent arterioles of ZFRs. These changes could narrow arteriolar lumens and reduce intraglomerular pressure, but they could cause also irreversible damage to the arterioles.

Effects of cyclohexenonic long-chain fatty alcohol in type 2 diabetic rat nephropathy.

We attempted to clarify the effects of cyclohexenonic long-chain fatty alcohol (CHLFA) on the alterations of type 2 diabetes-induced nephropathy. Forty-week-old male Goto-Kakizaki (GK) and Wistar rats were divided into four groups of 6 to 8 animals. Group A consisted of eight Wistar rats and served as an age-matched control group. Group B (7 GK rats) received no treatment and served as a diabetic group. Group C (6 GK rats) was treated daily with low-dose CHLFA (2 mg/ kg/body weight, subcutaneously) for 30 weeks, and Group D (6 GK rats) with high-dose CHLFA (8 mg/kg/body weight) for 30 weeks. At the end of the treatment period, urinary protein excretion, blood chemistry, renal histological, and immunohistological analyses were conducted. Although CHLFA administration did not influence serum glucose or insulin levels, it reversed diabetes-induced increases in urinary protein excretion and serum creatinine. Light microscopically, CHLFA treatment ameliorated the otherwise elevated glomerular sclerotic scores in the diabetic group.Immunohistochemically, increased expression of desmin and decreased expression of rat endothelial cell antigen-1 in the group with untreated diabetes both showed a reversal to control levels in the high-dose CHLFA treatment group. In conclusion, CHLFA may ameliorate type 2 diabetes-induced nephropathy.

Gap junctional intercellular communication in the juxtaglomerular apparatus.

The juxtaglomerular apparatus (JGA) is a specialized contact region between the glomerulus and the cortical thick ascending limb that plays an active role in the maintenance of ion homeostasis and control of blood pressure. The JGA accommodates several different cell types, including vascular smooth muscle cells, endothelial cells, mesangial cells, macula densa cells, and renin-secreting juxtaglomerular granular cells. These cells, with the exception of the macular densa cells, are tightly coupled by gap junctions. Gap junction-mediated intercellular communication in the JGA provides a pathway for signal transduction and coordination of multicellular functions. Disruption of cell-to-cell communication in the JGA results in altered preglomerular vascular tone and renin secretion. This review summarizes recent data about the roles of gap junctions in the JGA and illustrates how gap junction-mediated intercellular Ca(2+) signals determine physiological responses in the JGA.