Porphyromonas gingivalis infection in the oral cavity is associated with elevated galactose-deficient IgA1 and increased nephritis severity in IgA nephropathy.

BACKGROUND: The relationship between the major periodontal bacteria, Porphyromonas gingivalis, and the pathogenesis of IgA nephropathy (IgAN)-particularly with respect to galactose-deficient IgA1 (Gd-IgA1)-has not been fully elucidated. METHODS: Saliva samples from 30 IgAN patients and 44 patients with chronic kidney disease (CKD) were subjected to analysis of P. gingivalis status via polymerase chain reaction using a set of P. gingivalis-specific primers. The associations between P. gingivalis presence and clinical parameters, including plasma Gd-IgA1, were analyzed in each group. RESULTS: Compared with the CKD group, the IgAN group demonstrated significantly higher plasma Gd-IgA1 levels (p < 0.05). Compared with the P. gingivalis-negative subgroup, the P. gingivalis-positive subgroup exhibited significantly higher plasma Gd-IgA1 levels in both IgAN and CKD patients (p < 0.05). Additionally, among IgAN patients, the P. gingivalis-positive subgroup displayed significantly higher plasma Gd-IgA1 and urine protein levels, compared with the P. gingivalis-negative subgroup (p < 0.05). With respect to renal biopsy findings, the frequencies of segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis were significantly greater in the P. gingivalis-positive subgroup than in the P. gingivalis-negative subgroup, according to the Oxford classification of IgAN (p < 0.05). CONCLUSION: Our findings suggest an association between the presence of P. gingivalis in the oral cavity and the pathogenesis of IgAN, mediated by increased levels of Gd-IgA1.

cnm-positive Streptococcus mutans is associated with galactose-deficient IgA in patients with IgA nephropathy.

The presence of Streptococcus mutans expressing Cnm protein encoded by cnm (cnm-positive S. mutans) in the oral cavity is associated with immunoglobulin A (IgA) nephropathy (IgAN). However, the precise mechanism by which cnm-positive S. mutans is involved in the pathogenesis of IgAN remains unclear. The present study evaluated glomerular galactose-deficient IgA1 (Gd-IgA1) to clarify the association between the presence of cnm-positive S. mutans and glomerular Gd-IgA1 in patients with IgAN. The presence of S. mutans and cnm-positive S. mutans was evaluated by polymerase chain reaction in saliva specimens from 74 patients with IgAN or IgA vasculitis. Immunofluorescent staining of IgA and Gd-IgA1 using KM55 antibody in clinical glomerular tissues was then performed. There was no significant association between the glomerular staining intensity of IgA and the positive rate of S. mutans. However, there was a significant association between the glomerular staining intensity of IgA and the positive rate of cnm-positive S. mutans (P < 0.05). There was also a significant association between the glomerular staining intensity of Gd-IgA1 (KM55) and the positive rate of cnm-positive S. mutans (P < 0.05). The glomerular staining intensity of Gd-IgA1 (KM55) was not associated with the positive rate of S. mutans. These results suggest that cnm-positive S. mutans in the oral cavity is associated with the pathogenesis of Gd-IgA1 in patients with IgAN.

Distribution of periodontopathic bacterial species between saliva and tonsils.

Periodontopathic bacteria cause an inflammatory disease localized in the periodontal tissue and are associated with various conditions in other body parts. The distribution of periodontopathic bacterial species in the tonsils is unknown, even though the tonsils are located close to the oral cavity, and inflammation of the tonsils causes various systemic diseases. We detected the major periodontopathic bacterial species residing in saliva and tonsil specimens from 25 subjects undergoing tonsillectomy. Nine of the ten major periodontopathic bacterial species were detected by polymerase chain reaction of tonsil specimens, among which Campylobacter rectus was the most common (80.0%), followed by Porphyromonas gingivalis (36.0%). The other seven types of periodontopathic bacterial species were distributed with 0% to 25.0% abundance in the tonsil specimens. C. rectus had a high detection rate in tonsil specimens (> 75.0%), regardless of whether it was detected in the corresponding saliva specimens. However, the detection rate for P. gingivalis in tonsil specimens was significantly higher in subjects with P. gingivalis-positive saliva (77.8%) than in those with P. gingivalis-negative saliva (6.3%; P < 0.001). Furthermore, 75.0% of P. gingivalis in tonsil specimens did not have the known fimA gene that encodes the 41-kDa filamentous appendage protein FimA, which is expressed on the cell surface of the bacteria. Our results suggest that certain periodontopathic bacterial species are detected in the tonsils either independently of or depending on their distribution in the oral cavity and may be involved in tonsil-related diseases.

Simultaneous Presence of Campylobacter rectus and Cnm-Positive Streptococcus mutans in the Oral Cavity Is Associated with Renal Dysfunction in IgA Nephropathy Patients: 5-Year Follow-Up Analysis.

BACKGROUND: The simultaneous presence of Streptococcus mutans expressing the Cnm protein encoded by cnm (i.e., cnm-positive S. mutans) and Campylobacter rectus in the oral cavity has been associated with proteinuria in patients with IgA nephropathy (IgAN). OBJECTIVES: The present study evaluated the relationship between renal function and oral bacteria in patients with IgAN over 5 years of follow-up. METHODS: The presence of C. rectus and cnm-positive S. mutans in saliva samples of 117 patients with IgAN was initially evaluated by polymerase chain reaction. Patients were then divided into four groups according to the results of C. rectus and cnm-positive S. mutans detection: group A: C. rectus (-), cnm-positive S. mutans (-); group B: C. rectus (+), cnm-positive S. mutans (-); group C: C. rectus (-), cnm-positive S. mutans (+); and group D: C. rectus (+), cnm-positive S. mutans (+). Clinical characteristics were prospectively followed for 5 years. RESULTS: Serum creatinine levels were significantly higher in group D than in group A over 5 years of follow-up. Additionally, the proportion of patients with an estimated glomerular filtration rate <45 mL/min increased over time; it was significantly greater in group D than in group A over 5 years of follow-up. CONCLUSION: These results suggest that the simultaneous presence of C. rectus and cnm-positive S. mutans in the oral cavity is associated with renal dysfunction in IgAN patients.

A rare case of proliferative glomerulonephritis with monoclonal IgG2 kappa deposit: a case report.

BACKGROUND: Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare monoclonal gammopathy of renal significance with dense deposits of monoclonal immunoglobulin. CASE PRESENTATION: We report a 78-year-old Japanese male patient with mild proteinuria and lower extremity edema. Monoclonal immunoglobulin could not be identified in his serum or urine. Although his bone marrow biopsy was negative, renal biopsy found features of membranoproliferative glomerulonephritis (MPGN) with deposition of monoclonal IgG2 kappa. Electron microscopy examination revealed non-organized electron-dense deposits in the subepithelial, and subendothelial mesangial regions. Steroid monotherapy was performed after diagnosis of PGNMID but complete remission was not achieved. CONCLUSION: PGNMID with IgG3 kappa deposits is the most common in cases with the histological feature of MPGN. There are few cases of PGNMID with IgG2 kappa deposits exhibiting MPGN. This report describes a very rare case of PGNMID with the histological feature of MPGN.

Cnm of Streptococcus mutans is important for cell surface structure and membrane permeability.

Streptococcus mutans, a Gram-positive facultative anaerobic bacterium, is a major pathogen of dental caries. The protein Cnm of S. mutans is involved in collagen binding, but its other biological functions are unknown. In this study, a Cnm-deficient isogenic mutant and a complementation strain were generated from a Cnm-positive S. mutans strain to help determine the properties of Cnm. Initially, comparison of the cell surface structure was performed by electron microscopy, which demonstrated that Cnm appears to be localized on the cell surface and associated with a protruding cell surface structure. Deep RNA sequencing of the strains revealed that the defect in Cnm caused upregulated expression of many genes related to ABC transporters and cell-surface proteins, while a few genes were downregulated. The amount of biofilm formed by the Cnm-defective strain increased compared with the parental and complemented strains, but the biofilm structure was thinner because of elevated expression of genes encoding glucan synthesis enzymes, leading to increased production of extracellular polysaccharides. Particular antibiotics, including bacitracin and chloramphenicol, had a lower minimum inhibitory concentration for the Cnm-defective strain than particular antibiotics, including bacitracin and chloramphenicol, compared with the parental and complemented strains. Our results suggest that S. mutans Cnm is located on the cell surface, gives rise to the observed protruding cell surface, and is associated with several biological properties related to membrane permeability.

Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis.

A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.

Relationship between IgA Nephropathy and Porphyromonas gingivalis; Red Complex of Periodontopathic Bacterial Species.

IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN.

Streptococcus mutans induces IgA nephropathy-like glomerulonephritis in rats with severe dental caries.

The mechanisms underlying immunoglobulin A nephropathy (IgAN), the most common chronic form of primary glomerulonephritis, remain poorly understood. Streptococcus mutans, a Gram-positive facultatively anaerobic oral bacterium, is a common cause of dental caries. In previous studies, S. mutans isolates that express Cnm protein on their cell surface were frequently detected in IgAN patients. In the present study, inoculation of Cnm-positive S. mutans in the oral cavities of 2-week-old specific-pathogen free Sprague-Dawley rats fed a high-sucrose diet for 32 weeks produced severe dental caries in all rats. Immunohistochemical analyses of the kidneys using IgA- and complement C3-specific antibodies revealed positive staining in the mesangial region. Scanning electron microscopy revealed a wide distribution of electron dense deposits in the mesangial region and periodic acid-Schiff staining demonstrated prominent proliferation of mesangial cells and mesangial matrix. These results suggest that IgAN-like glomerulonephritis was induced in rats with severe dental caries by Cnm-positive S. mutans.

Dental caries status is associated with arteriosclerosis in patients on hemodialysis.

BACKGROUND: We previously found that worse dental caries status was associated with high pulse pressure among patients on hemodialysis, indicating that such patients might have arteriosclerosis. In this study, we used abdominal computed tomography to evaluate arteriosclerosis in patients on hemodialysis and investigated the association between arteriosclerosis and dental caries status. We also prospectively examined risk factors associated with 2-year prognosis. METHODS: The dental caries and periodontal disease statuses of 80 patients on hemodialysis were evaluated using the decayed, missing, or filled teeth (DMFT) index, and periodontal pocket depth, respectively. The aortic calcification index was semiquantitatively measured using computed tomography images of the abdominal aorta. Clinical data were also analyzed after all patients on hemodialysis provided written, informed consent to participate in the study. RESULTS: Regression analysis demonstrated a significant correlation between the DMFT and aortic calcification indexes. Multiple regression analysis showed that the DMFT index was significantly correlated with the aortic calcification index, following adjustment for age, sex, and dialysis period. Thirteen of the 80 patients died during the 2-year follow-up period; logistic regression analysis showed that mortality rate was significantly associated with the aortic calcification index, but not the DMFT index. However, periodontal pocket depth was not correlated with the aortic calcification index. CONCLUSION: These findings suggest that worse dental caries status could be associated with arteriosclerosis among patients on hemodialysis, which may indirectly affect the prognosis of arteriosclerosis in these patients.

Intravenous administration of Streptococcus mutans induces IgA nephropathy-like lesions.

BACKGROUND: IgA nephropathy (IgAN) is one of the most frequently occurring types of chronic glomerulonephritis. Previous analyses have revealed that a major pathogen of dental caries, Streptococcus mutans [which expresses collagen-binding protein (Cnm) on its surface], is involved in the pathogenesis of IgAN. METHODS: Cnm-positive S. mutans isolated from a patient with IgAN was intravenously administered to specific pathogen-free Sprague-Dawley rats to evaluate their kidney conditions. RESULTS: The urinary protein level of the S. mutans group reached a plateau at 30 days, with increased numbers of mesangial cells and an increased mesangial matrix. The numbers of rats with IgA-positive and/or C3-positive glomeruli were significantly greater in the S. mutans group than in the control group at 45 days (P < 0.05). Electron microscopy analyses revealed electron-dense depositions in the mesangial area among rats in the S. mutans group. There were significantly more CD68-positive cells (macrophages) in the glomeruli of the S. mutans group than in the glomeruli of the control group during the late phase (P < 0.05), similar to the findings in patients with IgAN. CONCLUSION: Our results suggested that intravenous administration of Cnm-positive S. mutans caused transient induction of IgAN-like lesions in rats.

Possible link between dental diseases and arteriosclerosis in patients on hemodialysis.

BACKGROUND: Patients on hemodialysis must undergo this procedure at a hospital three times weekly and might be unable to visit a dentist. In addition, dentists might hesitate to provide oral care because such patients tend to bleed because they are medicated with anticoagulants, are susceptible to bacterial infections, and might have unusual drug reactions. We postulated that patients on hemodialysis have worse oral status than healthy people, which in turn might predispose such patients to systemic complications. METHODS: We compared the status of dental caries and periodontal diseases among 80 patients on hemodialysis and 76 healthy individuals (controls) using the decayed, missing, or filled teeth (DMFT) index, total number of C4 teeth (destruction of the entire tooth crown), and periodontal pocket depth. Clinical data were analyzed after all patients on hemodialysis and controls provided written, informed consent to participate in the study. RESULTS: Total number of C4 teeth (p = 0.021), missing teeth (MT) index (p = 0.0302), and DMFT index score ≥ 24 (p = 0.017) were significantly higher in patients on hemodialysis than controls. Pulse pressure (p = 0.0042) and the prevalence of a history of heart disease such as angina pectoris and acute myocardial infarction (p = 0.029) were higher in patients on hemodialysis with higher (≥ 24) than lower (< 24) DMFT index scores. Periodontal pocket depth was not significantly different between these two groups. CONCLUSION: Worse status of dental caries is possibly associated with arteriosclerosis among patients on hemodialysis.

Specific strains of Streptococcus mutans, a pathogen of dental caries, in the tonsils, are associated with IgA nephropathy.

Streptococcus mutans is known to be a major causative agent of dental caries, and strains expressing the cell surface collagen-binding Cnm protein contribute to the development of several systemic diseases. A relationship between tonsillar immunity and glomerulonephritis has been recognized in IgA nephropathy (IgAN), and specific pathogens may have effects on tonsillar immunity (mucosal immunity). Here, we present findings showing a relationship between the presence of Cnm-positive S. mutans strains in the tonsils of IgAN patients and IgAN condition/pathogenesis. Analyses of tonsillar specimens obtained from patients with IgAN (n = 61) and chronic tonsillitis (controls; n = 40) showed that the Cnm protein-positive rate was significantly higher in IgAN patients. Among IgAN patients, the tonsillar Cnm-positive group (n = 15) had a significantly higher proportion of patients with high urinary protein (>1.5 g/gCr) and lower serum albumin level than the Cnm-negative group (n = 46). Additionally, Cnm protein and CD68, a common human macrophage marker, were shown to be merged in the tonsils of IgAN patients. These findings suggest that Cnm-positive S. mutans strains in the tonsils may be associated with severe IgAN.

Campylobacter rectus in the Oral Cavity Correlates with Proteinuria in Immunoglobulin A Nephropathy Patients.

BACKGROUND: Periodontitis-related pathogens, such as Campylobacter or Treponema species, have recently been shown to be associated with immunoglobulin A nephropathy (IgAN). Some strains of Streptococcus mutans, a major pathogen of dental caries, harbour the cnm gene that encodes a collagen-binding protein (Cnm). This has also been demonstrated to be associated with urinary protein levels in IgAN patients. OBJECTIVES: The purpose of the present study was to analyse the association of IgAN with C. rectus, Treponema denticola and cnm-positive S. mutans in the oral cavity of humans. METHODS: The presence of C. rectus, T. denticola and cnm-positive S. mutans strains in saliva samples of 117 IgAN patients and 56 healthy controls was evaluated by PCR, and the subjects' clinical parameters were analysed. RESULTS: C. rectus was significantly more prevalent in the IgAN group than in the control group (p < 0.05). The C. rectus-positive group was significantly associated with proteinuria in the IgAN group (p < 0.05). In addition, the C. rectus-positive and cnm-positive S. mutans group was shown to be more closely associated with urinary protein levels than the other groups (p < 0.0083). CONCLUSION: Our results suggest that harbouring C. rectus in the oral cavity could be associated with proteinuria in IgAN patients.

Presence of Streptococcus mutans strains harbouring the cnm gene correlates with dental caries status and IgA nephropathy conditions.

Streptococcus mutans is a major pathogen of human dental caries. Strains harbouring the cnm gene, which encodes Cnm, a collagen-binding protein, contribute to the development of several systemic diseases. In this study, we analysed S. mutans strains isolated from the oral cavity of immunoglobulin (Ig)A nephropathy (IgAN) patients to determine potential relationships between cnm and caries status as well as IgAN conditions. Saliva specimens were collected from 109 IgAN patients and the cnm status of isolated S. mutans strains was determined using PCR. In addition, the dental caries status (decayed, missing or filled teeth [DMFT] index) in patients who agreed to dental consultation (n = 49) was evaluated. The DMFT index and urinary protein levels in the cnm-positive group were significantly higher than those in the cnm-negative group (p < 0.05). Moreover, the urinary protein levels in the high DMFT (≥15) group were significantly higher than those in the low DMFT (<15) group (p < 0.05). Our results show that isolation of cnm-positive S. mutans strains from the oral cavity may be associated with urinary protein levels in IgAN patients, especially those with a high dental caries status.

Distribution of Streptococcus mutans strains with collagen-binding proteins in the oral cavity of IgA nephropathy patients.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis; however, its precise initiating pathogenesis remains unclear. Streptococcus mutans is a major pathogen of human dental caries. S. mutans strains with the cnm gene encoding Cnm, a collagen-binding protein, have been reported to contribute to the development of systemic diseases. However, the contribution of S. mutans with Cnm in the development of IgAN has not been reported. The aim of this study was to investigate the prevalence of cnm-positive S. mutans in IgAN patients and clarify the effects of cnm-positive S. mutans on the histological pathology of IgAN. METHODS: We identified the cnm gene in S. mutans isolated in saliva specimens, which were collected from IgAN patients (n = 53) and control subjects (n = 50). We evaluated the collagen-binding properties of S. mutans in IgAN patients and controls. The clinical parameters and histological scores were also assessed in IgAN patients. RESULTS: The rates of S. mutans isolation in IgAN and control groups were 84.0 and 84.9 %, respectively, not significantly dfferent. cnm-positive strains were significantly more prevalent in the IgAN group than in controls (32.1 vs. 14.0 %, p < 0.05). With regard to collagen-binding assays, the binding rates of cnm-positive strains were significantly higher in the IgAN group than in controls (96.6 vs. 30.0, p < 0.05). In addition, the segmental glomerulosclerosis scores were significantly higher in cnm-positive patients with IgAN than in cnm-negative patients with IgAN (0.94 vs. 0.57, p < 0.05). CONCLUSION: cnm-positive S. mutans strains are potentially associated with the pathogenesis of IgAN.

A case of anaphylactoid reaction to acetate in acetate-containing bicarbonate dialysate.

A 35-year-old man with end-stage kidney disease due to chronic glomerulonephritis was admitted to our hospital to start maintenance hemodialysis (HD). One hour after starting the first session of HD, he experienced general pruritus, urticaria, and dyspnea. Signs and symptoms were resolved by discontinuing HD and administrating an antihistamine drug; HD-associated anaphylactoid reactions were therefore suspected. Over the next few HD sessions, we changed the dialysis membrane, anticoagulant, HD circuit and needle, in that order, but general pruritus and urticaria again appeared within 3 h after starting each session of HD. Finally, when we changed the dialysate from acetate-containing bicarbonate dialysate to acetate-free bicarbonate dialysate, urticaria was clearly less than that seen in previous HD sessions, and subsided after discontinuation of HD. Subsequently, 20 mg of oral prednisolone (PSL) was administered 1 h before starting HD, and the patient did not experience general pruritus, urticaria, or dyspnea after starting the session. When administered acetate-containing bicarbonate dialysate after oral PSL pretreatment, the patient again experienced general pruritus, urticaria and dyspnea. Few reports have been published on the occurrence of anaphylactoid reactions during HD using acetate dialysate. We report a rare case of anaphylactoid reactions with acetate in acetate-containing bicarbonate dialysate that were reduced with the use of acetate-free bicarbonate dialysate and oral PSL pretreatment.

GIV/girdin links vascular endothelial growth factor signaling to Akt survival signaling in podocytes independent of nephrin.

Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα-interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases.

The amelioration of renal damage in Skp2-deficient mice canceled by p27 Kip1 deficiency in Skp2-/- p27-/- mice.

SCF-Skp2 E3 ubiquitin ligase (Skp2 hereafter) targets several cell cycle regulatory proteins for degradation via the ubiquitin-dependent pathway. However, the target-specific physiological functions of Skp2 have not been fully elucidated in kidney diseases. We previously reported an increase in Skp2 in progressive nephropathy and amelioration of unilateral ureteral obstruction (UUO) renal injury associated with renal accumulation of p27 in Skp2(-/-) mice. However, it remains unclear whether the amelioration of renal injury in Skp2(-/-) mice is solely caused by p27 accumulation, since Skp2 targets several other proteins. Using Skp2(-/-)p27(-/-) mice, we investigated whether Skp2 specifically targets p27 in the progressive nephropathy mediated by UUO. In contrast to the marked suppression of UUO renal injury in Skp2(-/-) mice, progression of tubular dilatation associated with tubular epithelial cell proliferation and tubulointerstitial fibrosis with increased expression of collagen and α-smooth muscle actin were observed in the obstructed kidneys in Skp2(-/-)p27(-/-) mice. No significant increases in other Skp2 target proteins including p57, p130, TOB1, cyclin A and cyclin D1 were noted in the UUO kidney in Skp2(-/-) mice, while p21, c-Myc, b-Myb and cyclin E were slightly increased. Contrary to the ameliorated UUO renal injure by Skp2-deficiency, the amelioration was canceled by the additional p27-deficiency in Skp2(-/-)p27(-/-) mice. These findings suggest a pathogenic role of the reduction in p27 targeted by Skp2 in the progression of nephropathy in UUO mice.

Enhanced intrarenal receptor-mediated prorenin activation in chronic progressive anti-thymocyte serum nephritis rats on high salt intake.

Despite suppression of the circulating renin-angiotensin system (RAS), high salt intake (HSI) aggravates kidney injury in chronic kidney disease. To elucidate the effect of HSI on intrarenal RAS, we investigated the levels of intrarenal prorenin, renin, (pro)renin receptor (PRR), receptor-mediated prorenin activation, and ANG II in chronic anti-thymocyte serum (ATS) nephritic rats on HSI. Kidney fibrosis grew more severe in the nephritic rats on HSI than normal salt intake. Despite suppression of plasma renin and ANG II, marked increases in tubular prorenin and renin proteins without concomitant rises in renin mRNA, non-proteolytically activated prorenin, and ANG II were noted in the nephritic rats on HSI. Redistribution of PRR from the cytoplasm to the apical membrane, along with elevated non-proteolytically activated prorenin and ANG II, was observed in the collecting ducts and connecting tubules in the nephritic rats on HSI. Olmesartan decreased cortical prorenin, non-proteolytically activated prorenin and ANG II, and apical membranous PRR in the collecting ducts and connecting tubules, and attenuated the renal lesions. Cell surface trafficking of PRR was enhanced by ANG II and was suppressed by olmesartan in Madin-Darby canine kidney cells. These data suggest the involvement of the ANG II-dependent increase in apical membrane PRR in the augmentation of intrarenal binding of prorenin and renin, followed by nonproteolytic activation of prorenin, enhancement of renin catalytic activity, ANG II generation, and progression of kidney fibrosis in the nephritic rat kidneys on HSI. The origin of the increased tubular prorenin and renin remains to be clarified. Further studies measuring the urinary prorenin and renin are needed.