The level of HIF1α transcription is controlled by nuclear factor-κΒ,[37] but its activity is mainly controlled post-translation by an oxygen-mediated ubiquitination and degradation selleckchem controlled by the Von Hippel–Lindau tumor suppressor complex and by positive regulation via a TORC1-mediated phosphorylation.[38] The differentiation of naive T cells under hypoxic conditions has also been suggested to enhance

FOXP3 expression and the development of regulatory activity,[34] but it is not clear whether this is a direct effect of HIF1α on FOXP3 expression, or whether it is acting indirectly, as HIF1α activation can also inactivate mTOR.[39] Hypoxia is associated with raised levels of AMP within the cell, which activates AMP-activated protein kinase and consequently inhibits mTOR via tuberous sclerosis complex 1/2. Other sources of AMP that may activate this pathway are downstream of G protein signalling where the generated cAMP from ATP is subsequently broken down to AMP by cAMP phosphodiesterases. In addition, extracellular adenosine can generate Selumetinib in vivo cAMP via activation surface receptors

(e.g. the A2AR on T cells[40, 41]) or can be directly taken up by specific transporters[42] where, once inside the cell, it will be rapidly converted to AMP by adenosine kinase, one of the most abundant enzymes present in mammalian cells. Adenosine is particularly relevant to immune regulation, as TGF-β is able to induce in a range of haematopoietic cells the co-expression of two ectoenzymes, CD39 and CD73,[43] that are constitutively expressed

on Treg cells.[44] These enzymes act to convert extracellular sources of ATP, which is associated with Amisulpride inflammation and cell necrosis, into the anti-inflammatory product adenosine (Fig. 2). Although there is some evidence that this pathway may be relevant to tumours escaping immune surveillance,[45, 46] it remains, however, to be resolved just how important adenosine is as a component of the anti-inflammatory microenvironment within tolerated tissues. It has only recently become clear that tolerance can be maintained by Treg cells acting within a highly localized microenvironment to induce a state of acquired immune privilege.[47, 48] This can best be demonstrated in experiments where donor alloantigen-specific tolerance has been induced to a skin graft (e.g. by a short period of co-receptor blockade with anti-CD4 and anti-CD8 monoclonal antibodies), and then that tolerated graft is removed and re-transplanted onto a secondary recipient with no T cells of its own (e.g. a recombinase activating gene 1 knockout mouse). As expected, this skin graft is accepted by the secondary recipient because it has no T cells to cause rejection. If, however, we treat the recipient at the time of grafting with monoclonal antibodies that deplete or inactivate FOXP3+ Treg cells (e.g. anti-CD25, or anti-hCD2, if the original recipient carries the hCD2.

Data are presented as mean ± SEM, and differences were considered significant at P ≤ 0·05. We infected 129/B6 mice lacking the IFN-α/βR (a common receptor for all type I IFNs) in the right hind footpad with 5 × 106 stationary-phase L. mexicana promastigotes and followed the course of lesion progression alongside infected WT 129/B6 mice (Figure 1a). The course of lesion development was not significantly different in IFN-α/βR Dorsomorphin KO and WT mice, with lesion sizes plateauing around 10–15 weeks post-infection. Parasite loads at 4, 12 and 23 weeks post-infection were

indistinguishable in WT and KO mice, with parasite burdens reaching a peak by 12 weeks post-infection at approximately 108 parasites/lesion (Figure 1b). We next wished to examine the immune response of IFN-α/βR KO and WT mice infected with L. mexicana. At various times, we harvested the draining lymph nodes and performed antigen-induced recall responses. At 4 weeks of infection, the IFN-γ response was 4·1-fold lower in IFN-α/βR KO mice than in WT mice (Figure 2a) indicating that IFN-α/β signalling may help encourage a partially protective IFN-γ response. However, by

17 weeks of infection, the IFN-γ response had declined in WT mice, with both WT and IFN-α/βR KO mice having very low IFN-γ Romidepsin research buy responses (Figure 2a). Antigen-induced IL-4 responses were very low and did not differ between IFN-α/βR KO and WT mice (data not shown). In agreement with the lack of any change in parasite burdens, nitric oxide production (as measured by nitrite) in the recall response supernatants,

were not different in IFN-α/βR KO and WT mice at 4 or 23 weeks post-infection (Figure 2b). IL-10 has been shown to suppress a protective Th1 response to L. mexicana infection, as IL-10 KO mice are resistant to this infection (4). The antigen-induced responses of draining LN cells from IFN-α/βR KO and WT mice were also examined for IL-10 production. We found that the IL-10 response was diminished in the KO mice as compared with WT mice, indicating Protirelin that type I IFNs may stimulate IL-10 production, thus giving IFN-α/β an immunosuppressive role (Figure 2c). At 4 weeks, there may have been less IL-10 (2·2-fold) in the KO mice, although this did not quite reach statistical significance (P = 0·09), but by 17 weeks, this was highly significant (P = 0·0002), with IFN-α/βR KO mice having 21-fold less IL-10 from draining LN cells than WT mice. Flow cytometry analysis demonstrated that a vast majority (88–89%) of IL-10+ cells were T cells in both WT and KO mice (Figure 3a, Table 1). Of the CD4+ T cells, 80–87% of IL-10+ cells were CD25+ (Table 1); CD25+CD4+ cells include Treg cells as well as newly activated effector cells. We did find that a lower percentage of CD25+CD4+CD3+ cells from IFN-α/βR KO mice were expressing IL-10 than in WT mice, although this did not quite reach statistical significance (Figure 3b, Table 1).

For immunophenotypic analysis, the Flk-1+ MSCs were detached and washed with phosphate-buffered saline (PBS) containing 0·5% BSA (Sigma) and incubated with fluorescein isothiocyanate (FITC) or phycoerythrin (PE)-labelled primary antibodies for 30 min at 4°C. To detect intracellular antigens, we fixed cells in 4% paraformaldehyde for 15 min at 4°C and then permeabilized them with 0·1% saponin (Sigma) for 1 h at room

temperature. Same-species, same-isotype FITC-labelled or PE-labelled immunoglobulin (Ig)G1 were used as negative controls. Finally, cells were washed twice with PBS containing 0·5% BSA and resuspended in 0·5 ml PBS for fluorescence activated cell sorter (FACS) analysis. Analysis was performed on a Beckman GDC-0449 molecular weight Coulter flow cytometer. DBA-1 mice were obtained from the Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences. Collagen-induced arthritis (CIA) was produced in 8–10-week-old male DBA-1 mice, as described previously [20]. Briefly, bovine type

II collagen (CII; Sigma) was emulsified with an equal volume of Freund’s complete adjuvant. Mice were injected at the base of the tail with 100 µl of emulsion containing 100 µg of collagen. On day 21, the mice received a booster injection of collagen emulsion in Freund’s incomplete adjuvant. Flk-1+ MSCs (1–2 × 106 cells in 0·3 ml PBS) were infused intravenously on either day 0 (day 0 group) or day 21 (day 21 group). Development of CIA was assessed twice a week. Paw swelling click here was assessed by measuring the thickness of the hind-paws using a caliper. For better comparison, we averaged the paw swelling increase on days 32, 35, 39, 43 and 49, respectively, which took into account most of the disease process. The symptom score Sclareol was assessed using the following system, as reported previously [20]; briefly, grade 0: no swelling; grade 1: ≥ 0·1 mm increase in paw swelling; grade 2: ≥ 0·2 mm increase in paw swelling; grade 3: extensive swelling (≥ 0·3 mm

increase in paw swelling) with severe joint deformity; and grade 4: pronounced swelling (≥ 0·45 mm increase in paw swelling) with pronounced joint deformity. On day 50, mice were anaesthetized for radiographic examination. The mice were then killed and limbs were fixed in 10% formalin, sections were prepared, and stained with haematoxylin and eosin (H&E) for histological assessment. Splenocytes were isolated by mechanical dissociation, followed by red blood cell lysis [10 min in NH4Cl (8·4 g/l)/potassium hydrogen carbonate (KHCO3) (1 g/l) buffer at 4°C]. Responder splenocytes were cultured in RPMI-1640 medium containing 10% FBS, incubated with 5 µg/ml concanavalin A (ConA; Sigma) for T cell stimulation or 25 µg/ml lipopolysaccharide (LPS; Sigma) for B cell stimulation. MSCs (10 Gy irradiated) were added to the splenocytes at ratios of 1:10 or 1:100.

There were no flap losses, but four flaps (20%) developed congestion at the tip of the https://www.selleckchem.com/products/Tigecycline.html flap that resolved without need for flap delay, leeching, or vasodilators. No patients developed complications with the donor site, and no patients underwent revisions. With a mean follow-up of 27.3 months (range: 19–38 months), all patients were pleased with their aesthetic outcomes and alive without recurrent disease. Conclusion:

The STAP flap is a pedicled perforator flap providing local “like” tissue that can be utilized for resurfacing of defects involving the anterior upper external ear with minimal donor site morbidity. © 2014 Wiley Periodicals, Inc. Microsurgery, 2014. “
“Objectives/Hypothesis: The primary objective of the study was to determine the frequency of intraoperative vasopressor administration among patients undergoing free tissue transfer for head and neck reconstruction, and the secondary objective was to determine the impact of intraoperative vasopressor on free tissue transfer outcomes, including the impact of cumulative vasopressor dose and timing of intraoperative vasopressor administration. JAK inhibitor Study design/Methods: A retrospective review was performed of all patients undergoing free tissue transfer for head and neck reconstruction at the University Health Network between 2004 to 2008. Results:

From 2004 to 2008 inclusive, 485 patients underwent 496 free tissue transfers for head and neck reconstruction. The complete failure rate was 2.2% (11 of 485 patients). The partial failure

rate was 1.4%, and the operative take-back rate for venous congestion or arterial thrombosis was Interleukin-2 receptor 1.6%. This gave a total major flap complication rate of 5.2%, which was used as the primary free tissue transfer outcome measure. Of the 485 patients who underwent free tissue transfer, 320 (66.0%) received intraoperative vasopressor. Of these patients, the majority (97.5%) received phenylephrine and/or ephedrine. There was no significant relationship between receiving intraoperative vasopressor and major free flap complications, which were defined as complete failure, partial failure, or operative take-back for venous congestion or arterial thrombosis. Conclusion: Intraoperative vasopressors are used routinely in free tissue transfer for the reconstruction of head and neck defects. The use of intraoperative vasopressors does not appear to adversely affect free tissue transfer outcomes. © 2011 Wiley Periodicals, Inc. Microsurgery, 2012. “
“Biosynthetic guides can be an alternative to nerve grafts for reconstructing severely injured peripheral nerves. The aim of this study was to evaluate the regenerative capability of chitosan tubes to bridge critical nerve gaps (15 mm long) in the rat sciatic nerve compared with silicone (SIL) tubes and nerve autografts (AGs).

(L.) amazonensis infection at 4th (528·49 cell/mm2) and 8th weeks PI (586·82 cell/mm2), and the control group (402·99 Ruxolitinib ic50 cell/mm2) (Figure 3). At 4th weeks PI, the Th2 cytokines production under specific antigenic stimulation showed that IL-4 levels in the L. (L.) amazonensis infection (139·61 pg/mL) were higher (P < 0·05) than those in the L. (V.) braziliensis infection (15·68 pg/mL), as well as at 8th

weeks PI when IL-4 was detected in the L. (L.) amazonensis group (14·45 pg/mL) and absence in mice infected with L. (V.) braziliensis (Figure 4a). In a similar way, the IL-10 levels were also higher (P < 0·05) in the L. (L.) amazonensis infection than in the L. (V.) braziliensis infection either at 4th (374·64 and 17·62 pg/mL) or at 8th (26·03 pg/mL and not detected) weeks PI (P < 0·05), respectively (Figure 4b). Concerning the production of Th1 cytokines, the IFN-γ levels were higher (P < 0·05) in the L. (V.) braziliensis infection than in the L. (L.) amazonensis infection either at 4th (174·41 pg/mL and 50·83 pg/mL) or at 8th (454·13 pg/mL and 30·16 pg/mL) weeks PI, respectively (Figure 4c). Production of the Th1/Th2 cytokines under nonspecific antigen stimuli (Concanavalin

A) showed similar profiles in both groups (Figure 4a–c). Concerning the control group, a check details nondetectable amount of cytokines was observed in the supernatant of lymph node cell cultures under either specific antigen or nonspecific

stimuli, according to the standard curve. The interaction process between Leishmania oxyclozanide parasites and DCs is complex and involves paradoxical functions, which can inhibit or stimulate T-cell response, leading to either progression or control of infection (18). It is assumed that not only the degree of DCs maturation but also specific subtypes and the compartmentalization of the antigen presentation are of critical interest to the quality of T-cell response (19). In the early phase of the Leishmania infection, besides macrophage, three types of DCs, in particular dDC, LC and inflammatory dendritic cells (iDC), can perform the function of antigen-presenting cells; however, it was demonstrated in murine cutaneous leishmaniasis that both dDC and iDC, but not resident LC in the epidermis, are responsible for the transportation of Leishmania antigens to the draining lymph nodes and stimulate the efficient Th1 immune response (9). Together with the above comments, it was demonstrated in the present work that Leishmania species can also be a crucial factor in priming DCs (dDC and LC) function for preferentially modulating an efficient Th1 or a defective Th2 immune responses. First, at 4th weeks PI, an increase in the cellular densities of both DCs populations in the skin of BALB/c mice infected with L. (L.) amazonensis (P < 0·05) in relation to those infected with L. (V.

In contrast, treatment with LGG wild-type results in an up-regulation of TLR-1, -2 and -4 compared to the dltD-treated group, highlighting the impact of inactivating the dltD gene. It is known that LTA molecules of certain bacteria can induce

proinflammatory signalling in macrophages by interaction with TLR-2 [56]. The exact role of d-alanylation in interaction of LTA with specific TLRs (TLR-2, TLR-6) and co-receptors (CD14, CD36) is not yet well established. Based on the crystal structure of TLR-2, the two acyl chains of LTA are suggested to interact with the lipid binding pocket of TLR-2, while the hydrophilic see more glycerophosphate chain is thought to be exposed to solvent or to interact with TLR-6 or another co-receptor of TLR-2 [57–59]. However, as LTA is a major cell wall compound of lactobacilli, changing the structure

of LTA by removing d-alanine residues might as well effect the interactions with other surface molecules and therefore cause pleiotropic effects that can impact indirectly on the anti-inflammatory capacity of the lactobacilli. Nevertheless, our results with the dltD mutant compared to the wild-type probiotic strain are in line with those of the study by Grangette et al. [36], where a dltB mutant of L. plantarum NCIMB8826 also showed, compared to the wild-type strain, an enhanced anti-inflammatory capacity in vitro in monocytes and in a trinitrobenzene sulphonic acid (TNBS) colitis model [60]. Y-27632 cell line Although both experimental set-ups (probiotic strains and colitis models) differ significantly, the study by Grangette et al. [36] and this study both suggest a key role for LTA modification in pro-/anti-inflammatory

effects of probiotic lactobacilli. Finally, the data from our experiments with LGG in the DSS-induced murine colitis model cannot be translated easily to the clinical setting, as introducing bacterial mutants in humans is not straightforward. However, it is interesting to mention that we also performed a pilot study with LGG in patients with active pouchitis (unpublished). TCL Two patients with acute pouchitis received daily 1011 CFU/ml of LGG (Valio, Helsinki, Finland) in capsules for 4 weeks in a randomized cross-over trial (4 weeks probiotics, 4 weeks placebo). In one of the patients, the symptoms of active pouchitis seemed to be exacerbated by the treatment. This study was discontinued and we decided to focus upon animal models, such as presented in this report, to understand more clearly the interaction of LGG with the intestinal mucosa. The data from our experiments, together with reports from other research groups on animal models [28,29] and Crohn’s disease patients [61], underline that caution should be taken when applying the wild-type strain of the well-known probiotic LGG in patients with active IBD.

Dialect variation may also be problematic for infant learners, who have less language experience. However, less is known about how such phonetic variation may impact infant speech perception, particularly word recognition (although, see Best, Tyler, Gooding, Orlando,

& Quann, 2009 for its impact on budding semantic representations). As infants gain experience with their ambient language, they attune to phonetic information that is linguistically relevant. Language experience may also help infants ignore information irrelevant to word identity, such as variation attributable to gender, affect, and accent (foreign and dialectal). From an early age, infants exhibit some ability to deal with irrelevant speaker LY2157299 research buy variability. Two-month-olds detect a syllable

change when produced by multiple speakers (Jusczyk, Pisoni, & Mullenix, 1992) and 6-month-olds discriminate a phonetic contrast between vowels, despite variability across speaker age and gender (Kuhl, 1979, 1983). Although infants can cope with linguistically irrelevant variability in sound discrimination, this ability does not translate to word recognition. Indeed, 7.5-month-olds fail to recognize a word when spoken by two speakers with dissimilar voices (e.g., male versus female; Houston & Jusczyk, 2000) and the same word spoken in different affective states (e.g., happy versus neutral; Singh, Morgan, & White, 2004). It is not until Lenvatinib clinical trial 10.5 months that infants ignore irrelevant gender and affect variability Selleckchem KU57788 in word recognition (Houston & Jusczyk, 2000; Singh et al., 2004).

Surprisingly little is known, however, about whether infants can accommodate the linguistically irrelevant variation introduced by dialectal accent when recognizing words in fluent speech. Although infants as young as 5–7 months of age can discriminate different dialectal accents (Kitamura, Panneton, Deihl, & Notley, 2006; Nazzi, Jusczyk, & Johnson, 2000), it is unknown how the aspects that differ across accents impact word recognition. One exception is Schmale and Seidl (2009), where 9- and 13-month-olds were tested on their ability to generalize words from a native speaker of infants’ ambient dialectal accent (North Midland-American English) to a foreign-accented speaker (Spanish-accented English). Results showed that, although the 13-month-olds recognized words across these accents, 9-month-olds failed. The authors suggest that one explanation for this developmental pattern may relate to an increase in the flexibility of infants’ word representations, with older infants being better able to ignore linguistically irrelevant variation introduced by different accents.

Ten thousand iNKT cells were collected in RLT buffer with 1% of β-mercaptoethanol. mRNA was isolated using RNeasy Mini Kit (Qiagen) and reverse transcripted with Superscript III (Invitrogen). Quantitative-PCR was realized with SYBR Green (Roche) and analyzed with LightCycler 480 (Roche). Pancreatic islet cells were prepared as previously described 53. Pancreata were perfused with a solution containing collagenase P (Roche), dissected free from surrounding tissues and digested at 37°C for 10 min. Islets were then purified Dasatinib supplier on a Ficoll gradient and disrupted by adding cell dissociation buffer (GIBCO) for 10 min at 37°C. iNKT cells from spleen and mesenteric LNs of CD45.1+/+ CD90.1+/+

Vα14 Cα−/− NOD mice were enriched by negative selection and then sorted as CD4− or CD4+ CD1d-αGalCer tetramer+ cells. Sorted cell purity was >96%. CD62L+ BDC2.5 T cells were isolated from CD45.2+/+

CD90.1+/+ BDC2.5 Cα−/− NOD mice. Splenocytes were enriched in T cells by negative selection and CD62L+ cells were positively selected using biotinylated anti-CD62L mAb and Streptavidin microbeads (Miltenyi Biotec). CD62L+ BDC2.5 T-cell purity was >92%. Similar procedures were used for the reconstitution with NK1.1− or NK1.1+ CD4− iNKT cells. Donor cells were obtained from NK1.1 Vα14 Cα−/− NOD mice. At Staurosporine mw 2 wks of age, CD45.1+/+ CD90.1+/+ Cα−/− NOD mice were reconstituted i.v with 1.5×106 CD4− or CD4+ iNKT cells from CD45.1+/+ CD90.2+/+ Vα14 Cα−/− mice. Mice were injected i.p with PK136 mAb (50 μg/mouse of on days 15, 17, 26 and with 100 μg/mouse on day 32). At 6 wks of age, recipient mice were injected i.v with 104 naïve CD62L+ BDC2.5 T cells from CD45.2+/+ CD90.1+/+ BDC2.5 Cα−/− mice. Diabetes analysis was also performed in mice reconstituted with NK1.1− or NK1.1+ CD4− iNKT cells. In some experiments mice were injected i.p with 200 μg of blocking anti-mouse IL-17 Ab (CA028_00511) or isotype control (101.4) on days 0, 2, 4, 6 and 8 after BDC2.5 acetylcholine T cell transfer (day 0). Reagents were provided by UCB Celltech. Overt diabetes was

defined by two consecutive positive glucosuria tests and glycemia >200 mg/dL. Statistical analyses were performed with the nonparametric Mann–Whitney U test. The log-rank test was used for the comparison of diabetes incidence. The authors thank UCB Celltech for the generous gift of anti-IL-17 and isotype control reagents, L. Breton and the staff of the mouse facility for help in animal care and L. Ghazarian and J. Diana for critical reading of the manuscript. This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale and the Centre National pour la Recherche Scientifique, grant from ANR-09-GENO-023 to A. L.. Anne-Sophie Gautron and Yannick Simoni were supported by doctoral fellowships from the Ministère de l’Education Nationale et de la Recherche et Technique and from Région Île-de-France. Conflict of interest: The authors declare no commercial or financial conflict of interest.

Thus, tumor-infiltrating VX-809 price myeloid cells appear to be primed directly or indirectly by gut commensal bacterial LPS through the TLR4 receptor for responsiveness to the TLR9 ligand CpG-ODN. The overall composition of the fecal microbiota was also found to segregate mice that showed either high or low TNF responses to CpG-OGN. In particular, the abundance of several Gram-positive and Gram-negative bacterial species in the fecal microbiota was found to positively correlate with the response of tumor myeloid cells to CpG-ODN, whereas the abundance of certain commensal Lactobacillus species showed a negative

correlation [22]. The enhancement of the CpG-ODN response by the Gram-negative Alistipes shaii, and its attenuation by L. fermentum were directly demonstrated by in vivo association experiments [22]. In the same study, the effectiveness of the treatment PI3K inhibitor of mouse sterile subcutaneous transplanted tumor with the platinum compounds oxaliplatin and cisplatin

was also observed to be dramatically reduced in antibiotic-treated or GF mice compared with conventional mice [22]. Platinum compounds are cytotoxic by virtue of forming platinum-DNA adducts that primarily accumulate intrastrand cross-links, and these in turn inhibit proliferation and induce apoptosis, in part by recruitment of the ataxia telangiectasia and rad3-related kinase to the DNA lesion and p53 activation [168]. In

addition to their direct cytotoxic effect, oxaliplatin but not cisplatin has been shown to induce immunogenic cell death, which releases endogenous activators of inflammation, Olopatadine such as high-mobility group protein B1 and ATP, thus driving activation of antigen-presenting cells and antitumor T-cell immunity [169, 170]. In antibiotic-treated mice, although the formation of platinum adducts to tumor cell DNA was not impaired, a significant decrease in DNA damage and cytotoxicity compared with conventional mice was already observed at day 2 after treatment, suggesting that antibiotics administration had suppressed the early genotoxic effect of the drug rather than the inflammatory/immune activation induced by immunogenic cell death [22]. Clear evidence suggests that H2O2 is important for the DNA damage and apoptosis induction effected by platinum compounds [171]. Antibiotics treatment was shown to inhibit the oxaliplatin-induced enhanced expression of genes related to inflammation, and in particular to monocyte differentiation, activation, and function, whereas it prevented the oxaliplatin-induced downregulation of genes related to normal cellular function, such as metabolism, transcription, translation, and DNA replication [22].

The objective of this meta-analysis was to evaluate the associations between consumption of sugar-sweetened

and artificially sweetened soda and CKD. A literature search was performed using MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews from inception until 30 June 2014. Studies that reported odds ratios or hazard ratios comparing the risk of CKD in patients consuming significant amounts of either sugar-sweetened or artificially sweetened soda versus those who did not consume soda were included. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects, generic inverse variance method. Five studies were included in our analysis of the association between consumption of sugar-sweetened soda and CKD. The pooled RR of CKD in patients consuming sugar-sweetened soda was 1.58 (95% CI 1.00–2.49). Four studies were selected to assess the association between Akt inhibitor consumption of artificially sweetened soda and CKD. The pooled RR of CKD in patients consuming artificially sweetened soda was 1.33 (95% CI 0.82–2.15). Our study demonstrates statistically significant increased AZD0530 risks of CKD in

patients consuming sugar-sweetened soda, but not in patients consuming artificially sweetened soda. This finding suggests that sugar-sweetened soda consumption is associated with CKD and may impact clinical management and primary prevention of CKD in high-risk patients. “
“The

intrarenal renin-angiotensin system (RAS) has been reported to be activated in chronic proteinuria patients. This study aimed to compare intrarenal RAS activity between diabetic nephropathy (DN) and non-diabetic nephropathy (NDN) patients with overt proteinuria. A multicenter, cross-sectional study was conducted in 116 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] > 1 mg/mg Cr). To estimate intrarenal RAS activity we measured urinary excretion of angiotensinogen (uAGT) and renin (uRenin) in patients with DN (n = 38) and NDN (n = 78). Both natural logarithms of uAGT/urinary second creatinine (ln[uAGT/uCr]) and uRenin (ln[uRenin/uCr]) levels were significantly higher in patients with DN compared with those with NDN (ln[uAGT/uCr]: 4.16 ± 1.13 vs. 3.52 ± 1.21 in NDN, P = 0.007; ln[uRenin/uCr]: 5.66 ± 1.60 vs. 4.29 ± 1.48 in NDN, P < 0.001), when estimated glomerular filtration rate (eGFR) and uPCR showed no significant difference between the two groups (P > 0.05). In a subgroup analysis, according to amount of proteinuria, both uAGT and uRenin were higher in DN in patients with subnephrotic-range proteinuria (uPCR < 3.5 mg/mg Cr), as expected. However, in patients with nephrotic-range proteinuria (uPCR ≥ 3.5 mg/mg Cr), only uRenin was higher in DN compared to NDN. In a multiple regression analysis, diabetes maintained independent association with uRenin excretion.