Gene transfer of RANTES elicits autoimmune renal injury in MRL-Faslpr mice

Infiltrating macrophages and T cells are instrumental in autoimmune kidney destruction of MRL-Faslpr mice. We report that the β-chemokine RANTES, a chemoattractant for macrophages and T cells, is up-regulated in the MRL-Faslpr kidney prior to injury, but not normal kidneys (MRL-++, C3H-++) and increases with progressive injury. Furthermore, we establish an association between RANTES expression in the kidney and renal damage using a gene transfer approach. Tubular epithelial cells genetically modified to secrete RANTES infused under the renal capsule incites interstitial nephritis in MRL-Faslpr, but not MRL-++ or C3H-++ mice. RANTES recruits predominantly macrophages (Mø) and CD4+ and CD8+ T cells. In contrast, gene transfer of CSF-1, another molecule up-regulated simultaneously with RANTES in MRL-Faslpr kidneys, promotes the influx of Mø, CD4+ T cells and the unique double-negative (DN) T cells (CD4-,CD8-), which are prominent in diseased MRL-Faslpr kidneys. Thus, RANTES and CSF-1 recruit distinct T cell populations into the MRL-Faslpr kidney. In addition, delivery of RANTES and CSF-1 into the kidney of MRL-Faslpr mice causes an additive increase in pathology. We suggest that the complementary recruitment of T cell populations by RANTES (CD4, CD8) and CSF-1 (CD4, DN) promotes autoimmune nephritis in MRL-Faslpr mice

IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease

Macrophages (Mø) are integral in ischemia/reperfusion injury–incited (I/R-incited) acute kidney injury (AKI) that leads to fibrosis and chronic kidney disease (CKD). IL-34 and CSF-1 share a receptor (c-FMS), and both cytokines mediate Mø survival and proliferation but also have distinct features. CSF-1 is central to kidney repair and destruction. We tested the hypothesis that IL-34–dependent, Mø-mediated mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD. In renal I/R, the time-related magnitude of Mø-mediated AKI and subsequent CKD were markedly reduced in IL-34–deficient mice compared with controls. IL-34, c-FMS, and a second IL-34 receptor, protein-tyrosine phosphatase ζ (PTP-ζ) were upregulated in the kidney after I/R. IL-34 was generated by tubular epithelial cells (TECs) and promoted Mø-mediated TEC destruction during AKI that worsened subsequent CKD via 2 distinct mechanisms: enhanced intrarenal Mø proliferation and elevated BM myeloid cell proliferation, which increases circulating monocytes that are drawn into the kidney by chemokines. CSF-1 expression in TECs did not compensate for IL-34 deficiency. In patients, kidney transplants subject to I/R expressed IL-34, c-FMS, and PTP−ζ in TECs during AKI that increased with advancing injury. Moreover, IL-34 expression increased, along with more enduring ischemia in donor kidneys. In conclusion, IL-34-dependent, Mø-mediated, CSF-1 nonredundant mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD

Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis

Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchymal cells during kidney disease. To investigate whether MCP-1 promotes tubular and/or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and glomeruli were severely damaged in the MCP-1–intact strain (day 7). MCP-1 transcripts increased fivefold in MCP-1–intact mice. MCP-1 was predominantly localized within cortical tubules (90%), and most cortical tubules were damaged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, there was a marked reduction (>40%) in tubular injury in MCP-1–deficient mice (histopathology, apoptosis). MCP-1–deficient mice were not protected from glomerular injury (histopathology, proteinuria, macrophage influx). Macrophage accumulation increased adjacent to tubules in MCP-1–intact mice compared with MCP-1–deficient mice (70%, P < 0.005), indicating that macrophages recruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysaccharide-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, promotes TEC and not glomerular damage, and increases activated macrophages adjacent to TEC that damage TEC during NSN. Therefore, we suggest that blockage of TEC MCP-1 expression is a therapeutic strategy for some forms of kidney disease.published_or_final_versio

Submeter bathymetric mapping of volcanic and hydrothermal features on the East Pacific Rise crest at 9°50′N

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 8 (2007): Q01006, doi:10.1029/2006GC001333.Recent advances in underwater vehicle navigation and sonar technology now permit detailed mapping of complex seafloor bathymetry found at mid-ocean ridge crests. Imagenex 881 (675 kHz) scanning sonar data collected during low-altitude (~5 m) surveys conducted with DSV Alvin were used to produce submeter resolution bathymetric maps of five hydrothermal vent areas at the East Pacific Rise (EPR) Ridge2000 Integrated Study Site (9°50′N, “bull's-eye”). Data were collected during 29 dives in 2004 and 2005 and were merged through a grid rectification technique to create high-resolution (0.5 m grid) composite maps. These are the first submeter bathymetric maps generated with a scanning sonar mounted on Alvin. The composite maps can be used to quantify the dimensions of meter-scale volcanic and hydrothermal features within the EPR axial summit trough (AST) including hydrothermal vent structures, lava pillars, collapse areas, the trough walls, and primary volcanic fissures. Existing Autonomous Benthic Explorer (ABE) bathymetry data (675 kHz scanning sonar) collected at this site provide the broader geologic context necessary to interpret the meter-scale features resolved in the composite maps. The grid rectification technique we employed can be used to optimize vehicle time by permitting the creation of high-resolution bathymetry maps from data collected during multiple, coordinated, short-duration surveys after primary dive objectives are met. This method can also be used to colocate future near-bottom sonar data sets within the high-resolution composite maps, enabling quantification of bathymetric changes associated with active volcanic, hydrothermal and tectonic processes.This work was supported by an NSF Ridge2000 fellowship to V.L.F. and a Woods Hole Oceanographic Institution fellowship supported by the W. Alan Clark Senior Scientist Chair (D.J.F.). Funding was also provided by the Censsis Engineering Research Center of the National Science Foundation under grant EEC-9986821. Support for field and laboratory studies was provided by the National Science Foundation under grants OCE-9819261 (D.J.F. and M.T.), OCE-0096468 (D.J.F. and T.S.), OCE-0328117 (SMC), OCE-0525863 (D.J.F. and S.A.S.), OCE-0112737 ATM-0427220 (L.L.W.), and OCE- 0327261 and OCE-0328117 (T.S.). Additional support was provided by The Edwin Link Foundation (J.C.K.)

Biphasic increase in circulating and renal TNF-α in MRL-lpr mice with differing regulatory mechanisms

Biphasic increase in circulating and renal TNF-α in MRL-lpr mice with differing regulatory mechanisms. Tumor necrosis factor (TNF)-α: contributes to expansion of lymphocytes in neonatal mice and can accelerate renal injury. T cells induced by the lpr gene promote renal injury. However, the lpr gene alone is insufficient to cause renal damage, since MRL-lpr, but not C3H-lpr mice develop lupus nephritis. In this study, we examined the temporal expression of TNF-α in the kidney and circulation of mice (MRL and C3H) with the lpr gene and their congenic counterparts (++). We measured a bioactive TNF-α using L929 cells and tissue expression with an avidin-biotin immunoperoxidase method. A biphasic increase in circulating TNF-α in MRL-lpr mice was detected. There was an initial peak in neonatal mice (703 ± 208 pg/ml) which normalized by two months of age (87 ± 13 pg/ml) and reascended proportional to the severity of renal injury (non-proteinuric 570 ± 87, proteinuric; 1255 ± 135 pg/ml). In addition, there was only a single peak in neonatal C3H-lpr mice (1270 ± 318 pg/ml) with a nadir by six weeks of age (434 ± 52 pg/ml). In contrast, serum TNF-α was low in MRL-++ and C3H-++ mice (80 ± 3 and 95 ± 30 pg/ml), respectively. TNF-α expression in kidneys paralleled the serum pattern in MRL-lpr mice. Enhanced TNF-α expression was restricted to tubular epithelial cells (TEC) in neonatal MRL-lpr and C3H-lpr mice, and not detected in congenics. In adult mice, intrarenal TNF-α expression was more ubiquitous and was detected in glomeruli, vascular smooth muscle and perivascular infiltrating cells as well as TEC. In addition, TNF-α expression intensified in the kidneys in proportion to the severity of proteinuria. TNF-α was absent in age matched C3H-lpr, C3H-++ and MRL-++ mice. Additional studies indicated that: (1) neither MRL-lpr or C3H-++ TEC constitutively secreted substantial amounts of TNF-α and required a cytokine stimulation; and (2) the clearance of TNF-α via TNF-α receptors was similar in MRL-lpr, MRL-++ and C3H-++ mice, suggesting the increase of serum TNF-α was not a result of a defect in clearance. Thus, these results indicate two distinct mechanisms of TNF-α regulation in MRL-lpr mice: (1) neonatal up-regulation related to the lpr gene; and (2) an increase in mature mice proportional to the severity of lupus nephritis

IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis

IL-15, a T cell growth factor, has been linked to exacerbating autoimmune diseases and allograft rejection. To test the hypothesis that IL-15–deficient (IL-15(–/–)) mice would be protected from T cell–dependent nephritis, we induced nephrotoxic serum nephritis (NSN) in IL-15(–/–) and wild-type (IL-15(+/+)) C57BL/6 mice. Contrary to our expectations, IL-15 protects the kidney during this T cell–dependent immunologic insult. Tubular, interstitial, and glomerular pathology and renal function are worse in IL-15(–/–) mice during NSN. We detected a substantial increase in tubular apoptosis in IL-15(–/–) kidneys. Moreover, macrophages and CD4 T cells are more abundant in the interstitia and glomeruli in IL-15(–/–) mice. This led us to identify several mechanisms responsible for heightened renal injury in the absence of IL-15. We now report that IL-15 and the IL-15 receptor (α, β, γ chains) are constitutively expressed in normal tubular epithelial cells (TECs). IL-15 is an autocrine survival factor for TECs. TEC apoptosis induced with anti-Fas or actinomycin D is substantially greater in IL-15(–/–) than in wild-type TECs. Moreover, IL-15 decreases the induction of a nephritogenic chemokine, MCP-1, that attracts leukocytes into the kidney during NSN. Taken together, we suggest that IL-15 is a therapeutic for tubulointerstitial and glomerular kidney diseases