Autoimmune kidney diseases can cause glomerulonephritis and tubulointerstitial nephritis, which if unresolved, lead to progressive glomerulosclerosis and tubulointerstitial fibrosis. The IL-1 receptor (IL-1R1) is known to have divergent and cell-specific effects in kidney injury. We hypothesized that IL-1R1 would dampen pro-inflammatory activation of myeloid cells such that deletion of myeloid cell IL-1R1 would exacerbate autoimmune nephritis. Mice with myeloid cell-specific deletion of IL-1R1 (LysMCre(+) / Il1r1fl/fl - MKO) and littermate controls (LysMCre(-) / Il1r1fl/fl - MWT) were subjected to nephrotoxic serum (NTS) nephritis. MKO mice demonstrated worsened glomerular and tubular injury as indicated by increased albuminuria, glomerular injury scores, and kidney mRNA levels of kidney injury molecule (KIM)-1 (Havcr1) and neutrophil gelatinase-associated lipocalin (NGAL/Lcn2). We further found that myeloid IL-1R1 deficiency resulted in increased myeloid cell ER stress and expression of the heterodimeric cytokine Ebi3/Il27a (IL-27). IL-27 then induced increased type I IFN expression by kidney endothelial cells. In turn, anti-IL-27 limited type I IFN expression in endothelial cells and NTS nephritis, and anti-IFNAR1 therapy ameliorated glomerular and tubular injury in MKO mice. Thus, we demonstrated a myeloid cell-endothelial cell immunoregulatory axis whereby myeloid IL-1R1 activity constrained endothelial type I IFN generation to limit chronic kidney damage.

Although trivalent manganese (Mn(III)) species have been recognized as crucial intermediates in the degradation of organic contaminants by Mn oxides, quantitative research on their specific roles remains scarce. Our study investigated the degradation processes of an organic pollutant, Bisphenol A (BPA), by dissolved Mn(III) and Mn(III)-bearing oxides, and elucidated the differences of the underlying mechanisms and reaction pathways between several Mn oxides and dissolved Mn(III). Our results indicated that BPA degradation rates with Mn(III)-bearing oxides alone follow the order: delta-MnO2 >> gamma-MnOOH > Mn3O4. Adding pyrophosphate (PP) significantly enhanced BPA degradation by promoting the formation of Mn(III)-PP complexes and exposing more reactive sites, achieved through destabilizing the crystal structure and mitigating of Mn(II) readsorption, particularly in gamma-MnOOH and Mn3O4. Our kinetic model revealed that heterogeneous degradation by Mn oxides is the predominant reaction pathway, accounting for 61.4 %, 87.8 %, and 73.8 % of the total degraded BPA for delta-MnO2, gamma-MnOOH, and Mn3O4, respectively, even in the presence of significant amount of dissolved Mn(III) intermediates due to high PP concentrations. These results offer mechanistic details on BPA degradation by Mn oxides and the influence of ligand concentration, providing helpful insights for optimizing degradation strategies of organic pollutants.

Ferrihydrite (Fh) and transition metal ions such as Cu(II) are ubiquitous in natural and engineered aquatic systems, influencing pollutant degradation through Fenton-like processes. In contrast to previous studies focusing exclusively on either Cu(II)-catalyzed homogeneous reactions or iron oxide-mediated heterogeneous reactions, this work presents an integrated view of Cu(II)-Fh interactions under environmentally relevant pH conditions. We demonstrate that Cu(II) and Fh jointly establish a dual-oxidant system capable of generating both hydroxyl radicals (•OH) and Cu(III). These reactive species operate through spatially distinct mechanisms, leading to pollutant-specific degradation behaviors. Five organic compounds, including formate (FA), benzoic acid (BA), bisphenol A (BPA), dimethyl phthalate (DMP), and hydroxyethylidene diphosphonic acid (HEDP), were examined to elucidate the roles of mineral surface affinity and reactive species distribution. Adsorbed compounds (FA, BA and BPA) were primarily degraded via nonradical inner-sphere electron transfer at the Fh surface, with limited •OH involvement. In contrast, weakly adsorbing pollutant, HEDP, degradation was governed by •OH and Cu(III), while DMP, which exhibited negligible adsorption and minimal Cu(III) reactivity, proceeded mainly through •OH generated with the presence of adsorbed surface Cu(II). This affinity-differentiated oxidation paradigm highlights how pollutant structure, coordination chemistry, and interfacial redox dynamics jointly control degradation pathways in mineral-water systems. Cu(II) plays a dual catalytic role: enhancing radical formation and acting as a selective oxidant via Cu(III) for strongly complexing ligands. These findings advance the mechanistic understanding of Cu-enhanced heterogeneous Fenton systems and provide new insight into contaminant fate and transformation in redox-active aquatic environments.

Dendritic cells (DCs) are implicated in the progression of chronic kidney disease (CKD), and emerging evidence demonstrates that metabolic reprogramming profoundly influences DC differentiation and activation. Dynamin-related protein 1 (Drp1), a central regulator of mitochondrial fission, modulates mitochondrial metabolism; however, its role in DC-mediated immune responses remains unclear. To investigate the role of myeloid Drp1 in regulating DC function and CKD, we generate CD11c-specific Drp1 knockout mice (Drp1 MKO) by breeding Drp1 flox/flox with Cd11c-Cre mice. Drp1 expression was significantly reduced in splenic DCs (0.45 ± 0.01 vs. 1.0 ± 0.09 au; p <0.001) and BMDCs (0.20 ± 0.003 vs. 1.0 ± 0.009 au; p <0.001) from Drp1 MKO compared to wild-type (WT) mice. At baseline, Drp1 MKO mice had normal kidneys and similar renal immune cell profiles compared WT mice. However, following nephrotoxic serum (NTS)-induced CKD, Drp1 MKO mice showed higher mortality (50% vs. 10%; p =0.057), elevated BUN levels (178 ± 23 vs. 91 ± 14 mg/dL; p<0.05), and more severe kidney injury and inflammation, as corroborated by increased mRNA expression of kidney injury and inflammation markers, including Lcn2 (3.0 ± 0.54 vs. 1.0 ± 0.26 au; p =0.015), Havcr1 (5.3 ± 1.4 vs. 1.0 ± 0.3 au; p =0.024), Fn1 (1.6 ± 0.17 vs. 1.0 ± 0.19 au; p =0.068), Tnf (3.5 ± 0.71 vs. 1.0 ± 0.23 au; p =0.015), and Il1b (2.3 ± 0.44 vs. 1.0 ± 0.40 au; p =0.077). Costimulatory molecules on DCs provide the second signal required for effective T cell priming and promote clonal expansion of T cells. During NTS-induced CKD, Drp1 MKO kidneys exhibited increased numbers of CD86 + DCs (1.92 ± 0.17 vs. 1.15 ± 0.25 X10 4 /g; p=0.035) and T cells (20.2 ± 1.2 vs. 13.0 ± 1.7 X10 4 /g; p=0.01) compared to WT mice. Furthermore, Drp1 MKO kidneys had elevated numbers of effector memory T cells (CD44 hi CD62 lo , 10.01 ± 0.60 vs. 7.23 ± 0.98 X10 4 /g; p=0.047) and tissue-resident memory T cells (CD69 + , 6.63 ± 0.38 vs. 4.21 ± 0.39 X10 4 /g; p=0.002) compared to WT controls. These findings suggest that Drp1 in DCs protects against NTS-induced CKD by limiting DC-mediated T cell activation.

The cycling processes of elemental manganese (Mn), including the redox reactions of dissolved Mn(III) (dMn(III)), directly and indirectly influences the biogeochemical processes of many elements. Though increasing evidence indicates the widespread presence of dMn(III) mediates the fate of many elements, its role may be currently underestimated. There is both a lack of clear understanding of the historical research framework of dMn(III) and a systematic overview of its geochemical properties and detection methods. Therefore, the primary aim of this review is to outline the understanding of dMn(III) in multiple fields, including soil science, analytical chemistry, biochemistry, geochemistry, and water treatment, and summarize the formation pathways, species forms, and detection methods of dMn(III) in aquatic systems. This review considers how the characteristics of dMn(III), the intermediate formed in the single-electron reaction processes of Mn(II) oxidation and Mn(IV) reduction, determines its participation in environmental geochemical processes. Its widespread presence in diverse water systems and active redox properties coupling with various elements confirm its significant role in natural elemental geochemistry cycle and artificial water treatment processes. Therefore, further investigation into the role of dissolved Mn(III) in aquatic systems is warranted to unravel unexplored coupled elemental redox reaction processes mediated by dissolved Mn(III), filling in the gaps in our understanding of manganese environmental geochemistry, and providing a theoretical basis for recognizing the role of dMn(III) role in water treatment technologies.

Key Points Proximal tubular TNF aggravates kidney injury and fibrogenesis in aristolochic acid nephropathy. Tubular TNF disrupts the cell cycle in injured tubular epithelial cells. TNF-mediated toxic renal injury is independent of systemic immune responses. Background Aristolochic acid nephropathy (AAN) presents with tubular epithelial cell (TEC) damage and tubulointerstitial inflammation. Although TNF- α regulates cell apoptosis and inflammatory responses, the effects of tubular TNF in the progression of AAN require elucidation. Methods Floxed TNF mice on the 129/SvEv background were crossed with PEPCK-Cre mice to generate PEPCK-Cre + TNF flox/flox (TNF PTKO) mice or bred with Ksp-Cre mice to generate KSP-Cre + TNF flox/flox (TNF DNKO) mice. TNF PTKO, TNF DNKO, and wild-type controls (Cre negative littermates) were subjected to acute and chronic AAN. Results Deletion of TNF in the proximal but not distal nephron attenuated kidney injury, renal inflammation, and tubulointerstitial fibrosis after acute or chronic aristolochic acid (AA) exposure. The TNF PTKO mice did not have altered numbers of infiltrating myeloid cells in AAN kidneys. Nevertheless, kidneys from AA-treated TNF PTKO mice had reduced levels of proteins involved in regulated cell death, higher proportions of TECs in the G0/G1 phase, and reduced TEC proportions in the G2/M phase. Pifithrin- α , which restores the cell cycle, abrogated differences between the wild-type and PTKO cohorts in G2/M phase arrest of TECs and kidney fibrosis after AA exposure. Conclusions TNF from the proximal but not the distal nephron propagates kidney injury and fibrogenesis in AAN in part by inducing G2/M cell cycle arrest of TECs.

Whereas the ubiquitin editor A20 limits NF-κB-mediated signaling in myeloid leukocytes, the functions of A20 in renal epithelial cells during hypertension have not been described. We recently found that A20 in the kidney tubule ameliorates hypertension and cardiac hypertrophy induced by chronic angiotensin (Ang) II infusion (500ng/kg/min) in mice. Here we report that following 3 weeks of hypertension, the kidneys of mice with tubular deletion of A20 in the kidney epithelium (“A20 iKKO” = A20 flox/flox Pax8-rtTA TetO-Cre + ) have augmented protein expression of the proximal tubular sodium transporter NHE3 (1.5±0.1 vs. 1.0±0.1; p <0.01) but similar levels of ENaC subunit expression in the collecting tubule ( p =NS for all 3 subunits) vs wild-type (WT) controls. Moreover, kidneys from A20 iKKO mice have upregulated mRNA levels for the T cell chemokine CCL5 (2.4±0.3 vs. 1.0±0.3; p <0.01) and higher proportions of effector memory CD8 + T cells (51.2±2.3 vs. 39.3±2.9 % of CD8 + ; p =0.013) compared to WTs despite similar numbers of effector memory T cells in the spleen ( p =NS). To examine whether A20 in the kidney attenuates hypertension by constraining tubular NHE3 expression, we bred A20 iKKO mice with an NHE3 flox/flox line, thereby generating mice with double A20 and NHE3 deletion in the kidney tubule (“Dual KKO”) mice. At baseline, kidneys from Dual KKO mice showed robust reductions in mRNA for A20 (0.5±0.1 vs. 1.0±0.1; p =0.022) and NHE3 (0.2±0.05 vs. 1.0±0.15; p =0.002) compared to WT littermates. During the first ten days of Ang II infusion, mean arterial pressures (MAPs) in the Dual KKO mice were lower than the MAPs previously recorded in our A20 iKKO cohort (129±3 vs. 152±4 mmHg; p <0.01). Moreover, during 3 weeks of Ang II infusion, Dual KKO and WT mice maintained similar MAPs (145±7 vs. 149±13 mmHg; p =0.78), and heart weight to body weight ratios (5.9±0.3 vs. 5.5±0.2 mg/g; p =0.37) in concomitant measurements. Thus, A20 in the kidney tubule blunts the chronic hypertensive response by curtailing NHE3 expression. Our data further suggest that A20 in the nephron can blunt renal inflammation without altering systemic T cell immunity. Stimulating the A20 signaling pathway in the kidney may thus attenuate NHE3-dependent hypertension without conferring attendant risks of global immunosuppression.

Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1β (IL-1β) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI.Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre+/IL-1R1fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre-/IL-1R1fl/fl–Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice.Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1β) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1β-induced tubular cell injury.Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.

The transcription factor Twist1 plays a vital role in normal development in many tissue systems and continues to be important throughout life. However, inappropriate Twist1 activity has been associated with kidney injury and fibrosis, though the underlying mechanisms involved remain incomplete. Here, we explored the role of Twist1 in regulating fibroblast behaviors and the development kidney fibrosis. Initially Twist1 protein and activity was found to be markedly increased within interstitial myofibroblasts in fibrotic kidneys in both humans and rodents. Treatment of rat kidney interstitial fibroblasts with transforming growth factor-β1 (a profibrotic factor) also induced Twist1 expression in vitro. Gain- and loss-of-function experiments supported that Twist1 signaling was responsible for transforming growth factor-β1-induced fibroblast activation and fetal bovine serum-induced fibroblast proliferation. Mechanistically, Twist1 protein promoted kidney fibroblast activation by driving the expression of downstream signaling proteins, Prrx1 and TNC. Twist1 directly enhanced binding to the promoter of Prrx1 but not TNC, whereas the promoter of TNC was directly bound by Prrx1. Finally, mice with fibroblast-specific deletion of Twist1 exhibited less Prrx1 and TNC protein abundance, interstitial extracellular matrix deposition and kidney inflammation in both the unilateral ureteral obstruction and ischemic-reperfusion injury-induced kidney fibrotic models. Inhibition of Twist1 signaling with Harmine, a β-carboline alkaloid, improved extracellular matrix deposition in both injury models. Thus, our results suggest that Twist1 signaling promotes the activation and proliferation of kidney fibroblasts, contributing to the development of interstitial fibrosis, offering a potential therapeutic target for chronic kidney disease.

The oxidative dissolution of As from arsenopyrite, one important arsenic mineral in reducing conditions, poses an environmental hazard to natural aquatic systems. The dissolution of arsenopyrite occurs slowly due to the surface precipitates of iron oxides in circumneutral oxic environments. However, the presence of natural ligands and coexisting metals may change the release of Fe species, which would be of critical importance to the dissolution of arsenopyrite. Here, we investigated the oxidative dissolution of arsenopyrite induced by pyrophosphate (PP) and dissolved Mn(III) species as a natural occurring Mn species with strong complexation affinity to PP. With the presence of PP, the formation of Fe(II)-PP complexes and its rapid oxidation to dissolved Fe(III)-PP species resulted in a substantial increase in the generation of hydroxyl radicals (•OH) under ambient dark conditions, contributing to faster dissolution of arsenopyrite and higher percentage of As(V) in the dissolved products. Dissolved Mn(III), though considered as an extra oxidant besides oxygen, unexpectedly acted as a radical scavenger for •OH and inhibited the production of As(V). Moreover, the oxidation of sulfur species differed in the two systems as significant formation of thiosulfate was observed with the presence of PP, which did not occur in the system with dissolved Mn(III). Overall, the effects of dissolved Mn(III) and PP on the dissolution of arsenopyrite and the subsequent transformation of Fe, As and S species have important implications for disentangling the interactions among these metastable elements, and for assessing their transport and environmental impacts in aquatic systems.

Chronic Kidney Disease (CKD) progression may be slowed or stopped with early diagnosis and intervention, so developing novel therapies is paramount. The Wnt acyl transferase porcupine (PORCN) regulates the secretion of all 19 Wnt ligand isoforms that propagate β-catenin signaling. We find that mice with deletion of PORCN from kidney epithelia (PORCN iKKO) had augmented kidney injury in the nephrotoxic serum nephritis (NTS) model of CKD, with higher BUNs (202 ± 12 vs. 101 ± 38, mg/dL; p<0.01), and renal mRNA levels for NGAL (6.1±1.14 vs. 1.0±0.35 au, p=0.0013), KIM-1(2.5±0.65 vs. 1.0±0.26 au, p=0.046), collagen I (2.4±0.31 vs. 1.0±0.38 au, p=0.025), and fibronectin (2.5±0.35 vs. 1.0±0.27 au, p=0.006) compared to wild-type (WT) controls. PORCN iKKOs also had upregulated renal protein levels for collagen I (1.5 ± 0.2 vs. 1.0 ± 0.1 au; p=0.01) and fibronectin (1.8 ± 0.3 vs. 1.0 ± 0.1 au; p<0.01), recapitulating the mRNA patterns. We also detected marked TNFα mRNA upregulation in the PORCN iKKO kidneys vs WTs during CKD (2.6±0.67 vs. 1.0±0.30 au, p=0.036). TNFα is a potent driver of renal injury and fibrosis, acting via TNFα receptor 1(TNFR1) to promote ROS generation. At day 14 of NTS, PORCN iKKO kidneys contained higher levels of the ROS metabolite, 8-isoprostane (2348 ± 718 vs. 486 ± 77, pg/mg kidney; p=0.02), and expressed higher levels of mitochondrial dysfunction markers, including Drp1 (1.26 ± 0.06 vs. 1.0 ± 0.04 au; p<0.01) and p62 (1.3 ± 0.09 vs. 1.0 ± 0.07 au; p=0.07). TNFR1 inhibition (R-7050, 12mg/kg, IP, every other day) reduced BUNs (94.13 ± 3 vs. 90.26 ± 4.1, mg/dL; p=0.46) and renal Drp1 protein levels (1.4 ± 0.17 vs. 1.0 ± 0.15 au; p=0.11) in the PORCN iKKO cohort to WT levels. In primary renal tubular cells (RTCs), TNFα treatment (50ng/ml, 12hrs) induced 8-isoprostane generation (387 ± 119 vs. 121 ± 39, pg/ml in medium; p=0.07), corroborating our in vivo studies. Moreover, treatment of the RTCs with the Drp1 inhibitor mdivi-1 (MD1, 10μm) for 12 hours attenuated TNFα-induced accumulation of fibronectin and collagen I. Our studies suggest that PORCN in renal epithelia protects against kidney damage by limiting TNFα induction, thereby diminishing Drp1-mediated mitochondrial dysfunction and ROS generation.

Significance Statement Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. Background Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. Methods To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. Results scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid–induced AKI by restoring VEGFA-dependent endothelial cell viability and density. Conclusions These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.

We recently reported that the ubiquitin-editing protein A20 in myeloid cells can limit the severity of hypertension. However, whether A20 in the kidney regulates renal injury without impacting systemic immune responses remains unclear. To address this question, we bred A20 flox/flox mice with the Pax8-rtTA and Tet-On lines, generating inducible renal epithelial cell A20 knockout mice (A20 iKKO). Mice with all 3 transgenes were used as the A20 iKKO group, whereas mice lacking the Pax8-rtTA or Tet-On transgene were wild-type (WT) controls. Before the experiments, mice were given 2mg/ml of doxycycline in water containing 5% (5 of 100) sucrose for 2 weeks so that A20 in renal tubular cells was ablated. 3 days after a single dose of cisplatin (20mg/kg), A20 iKKO mice exhibited more severe kidney injury compared to WTs (blinded injury score, 3.2±0.41 vs. 2.1±0.35 au, p=0.039). A20 iKKOs also had upregulated renal mRNA levels for NGAL (6.0±1.91 vs. 1.0±0.18 au, p=0.018) and KIM-1(3.3±1.2 vs. 1.0±0.29 au, p=0.07). Injured kidneys from the A20 iKKOs contained greater absolute numbers of T cells (123.6±8.5 vs. 53.8±4.7, x10 4 cells per gram kidney, p<0.001), macrophages (159.7±22.5 vs. 52.7±9.9, x10 4 cells per gram kidney, p<0.001), and dendritic cells (66.7±10.6 vs. 32.6±6.1, x10 4 cells per gram kidney, p=0.015) than WTs by flow cytometric analysis. In turn, mRNA levels for TNF-α (9.1±2.62 vs. 1.0±0.18 au; p=0.006) and IL-1β (4.1±1.06 vs. 1.0±0.13 au; p=0.009) were increased in the injured A20 iKKO injured kidneys vs WTs. Thus, A20 in the kidney epithelium protects against cisplatin-induced kidney injury by constraining renal immune cell accumulation and inflammatory cytokine release.

Background: Type 1 angiotensin (AT1) receptors are expressed on immune cells, and we previously found that bone marrow–derived AT1 receptors protect against Ang (angiotensin) II-induced hypertension. CD11c is expressed on myeloid cells derived from the bone marrow, including dendritic cells (DCs) that activate T lymphocytes. Here, we examined the role of AT1 receptors on CD11c+ cells in hypertension pathogenesis. Methods: Mice lacking the dominant murine AT1 receptor isoform, AT1a, on CD11c+ cells (dendritic cell [DC] AT1aR knockout [KO]) and wild-type (WT) littermates were subjected to Ang II-induced hypertension. Blood pressures were measured by radiotelemetry. Results: DC AT1aR KO mice had exaggerated hypertensive responses to chronic Ang II infusion with enhanced renal accumulation of effector memory T cells and CD40+ DCs. CCL5 (C-C motif chemokine ligand 5) recruits T cells into injured tissues, and CCR7 (C-C motif chemokine receptor 7) facilitates DC and T cell interactions in the kidney lymph node to allow T cell activation. DCs from the hypertensive DC AT1aR KO kidneys expressed higher levels of CCL5 and CCR7. mRNA expressions for CCR7 and tumor necrosis factor-α were increased in CD4+ T cells from the renal lymph nodes of DC AT1aR KO mice. During the second week of Ang II infusion when blood pressures between groups diverged, DC AT1aR KO mice excreted less sodium than WTs. Expressions for epithelial sodium channel subunits were increased in DC AT1aR KO kidneys. Conclusions: Following activation of the renin angiotensin system, AT1aR stimulation on DCs suppresses renal DC maturation and T cell activation with consequent protection from sodium retention and blood pressure elevation.

A thorough understanding of the complex redox coupling among manganese, arsenic, sulfur and oxygen in subsurface environments is still obscured by their metastable intermediate valances and speciation. Arsenic sulfide minerals may be disturbed by natural or anthropogenic activities, and encounter oxidants such as oxygen and reactive trivalent Mn species, and how these abiotic interactions impact the mineral dissolution and transformation of arsenic and sulfur species, remains unknown. In this study, we investigated the effects of dissolved Mn(III) and manganite (γ-MnIIIOOH) on the dissolution behaviors of orpiment (As2S3) and realgar (AsS) under anoxic and oxic conditions. Complementary control experiments were also performed with dissolved arsenite without reduced sulfur. Oxygen, dissolved Mn(III) or manganite did not induce the oxidation of dissolved arsenite within several weeks. Orpiment’s initial dissolution is a non-redox process releasing of arsenite and sulfide, and the three above oxidants promoted the dissolution of orpiment by rapid oxidation of dissolved sulfide. However, only when both dissolved Mn(III) and dissolved oxygen were present, substantial accumulation of arsenate and sulfate were observed. These results suggested the critical role of sulfur species in abiotic arsenic transformation and a synergetic effect of Mn and oxygen on sulfur oxidation. In contrast to orpiment, the dissolution of realgar was a redox reaction that involved the oxidation of As(II) to As(III) and the direct releasing of sulfide, which could be promoted by both dissolved oxygen and manganite. The effect of dissolved Mn(III) and oxygen on the formation of arsenate and sulfate was also clearly observed during the dissolution of realgar. Despite of the slow abiotic oxidation of dissolved arsenite to arsenate in the presence dissolved Mn(III) and oxygen, the coexistence of sulfide could enable rapid accumulation of arsenate, accompanied by substantial transformation to sulfate. The evidence of thioarsenic species in these experiments provided a plausible explanation as an alternative pathway for the oxidation of the two elements by dissolved Mn(III). These results provide new insights for the Mn-As-S cycling in redox transition environments.