The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the ...urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na
-dependent Cl
/HCO
exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl
/HCO
exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.
Abstract
Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. The stepwise hydrolysis ...of extracellular ATP by ectonucleotidases CD39 and CD73 generates adenosine, a potent immune suppressor. Here we report that human effector CD8 T cells contribute to adenosine production by releasing CD73-containing extracellular vesicles upon activation. These extracellular vesicles have AMPase activity, and the resulting adenosine mediates immune suppression independently of regulatory T cells. In addition, we show that extracellular vesicles isolated from the synovial fluid of patients with juvenile idiopathic arthritis contribute to T cell suppression in a CD73-dependent manner. Our results suggest that the generation of adenosine upon T cell activation is an intrinsic mechanism of human effector T cells that complements regulatory T cell-mediated suppression in the inflamed tissue. Finally, our data underscore the role of immune cell-derived extracellular vesicles in the control of immune responses.
Recently, a (pro)renin receptor has been identified which mediates profibrotic effects independent of angiotensin II. Because antihypertensive therapy induces renal injury in the clipped kidney of ...two kidney-1-clip hypertensive rats, we examined the regulation of renin and the (pro)renin receptor in this model. Hypertensive Goldblatt rats were treated with increasing doses of the vasopeptidase inhibitor AVE 7688 after which the plasma renin and prorenin as well as the renal renin and (pro)renin receptor expression were measured. The vasopeptidase inhibitor dose-dependently lowered blood pressure, which was associated with a massive increase in plasma prorenin and renin as well as increased renal renin expression. The (pro)renin receptor was upregulated in the clipped kidney of the Goldblatt rat indicating a parallel upregulation of renin and its receptor in vivo. Immunohistochemistry showed a redistribution of renin upstream from the glomerulus in preglomerular vessels and renin staining in tubular cells. Expression of the (pro)renin receptor was increased in the vessels and tubules. This upregulation was associated with thickening of renin-positive vessels and tubulointerstitial damage. We propose that renin and the (pro)renin receptor may play a profibrotic role in the clipped kidney of Goldblatt rats treated for hypertension.
The C57BL/6 mouse strain serves as the genetic background of many transgenic and gene knockout models; however, this strain appears to be resistant to hypertension-induced renal injury. We developed ...a new model of hypertensive end-organ damage in C57BL/6 mice by combining deoxycorticosterone acetate (DOCA) and salt with angiotensin II infusion. The systolic blood pressure (SBP) was significantly elevated in DOCA salt–angiotensin II mice compared to control mice or mice treated individually with DOCA salt or angiotensin II. Hypertensive glomerular damage, increased expression of profibrotic and inflammatory genes, albuminuria, tubular casts, increased plasma cholesterol, cardiac hypertrophy, and fibrosis were found in mice treated with DOCA salt–angiotensin II. The SBP in the angiotensin II-infused group was further increased by increasing the infusion rate; only mild injury was observed in these mice, suggesting that blood pressure was not a causal factor. Removal of DOCA and the angiotensin pump lowered blood pressure to normal; however, albuminuria along with the glomerular and cardiac damage did not completely resolve. Our study describes a new model of hypertensive end-organ damage and repair in C57BL/6 mice.
Podocytes play a major role in the initiation and progression of glomerular diseases and are a target of both immune-mediated and non-immune-mediated injury. To establish a mouse model of such ...injury, we preimmunized mice with Freunds adjuvant 5 days before intravenous injection of a rabbit polyclonal antibody directed against a murine podocyte cell line. For the next 7 weeks, we collected urine, serum, and kidney samples. Nephritic animals developed severe albuminuria, which was maximal on day 10. Histochemistry revealed diffuse mesangial matrix expansion. Mouse immunoglobulin G and complement were detected in a linear pattern along the glomerular filtration barrier and in the mesangial hinge region. Complement depletion, however, did not prevent proteinuria. Glomerular T cells were increased, whereas podocytes were significantly reduced. Glomerular foot processes were flattened in regions with mesangial matrix deposition as viewed by electron microscopy. Immunohistochemistry detected the injected anti-podocyte antibody exclusively at the glomerular tuft on all days examined. Immunoelectron microscopy localized the antibody to podocyte foot processes and the glomerular basement membrane, which was morphologically intact. This suggests that the podocyte was the main target of the antiserum. Our study establishes a new mouse model of immune-mediated podocyte injury.
γδ T cells are involved in the control of
infection, but their importance in protection compared to other T cells is unclear. We used a mouse model of systemic
infection associated with high ...bacterial load and persistence in the kidney. Infection caused fulminant accumulation of γδ T cells in the kidney. Renal γδ T cells acquired tissue residency and were maintained in high numbers during chronic infection. At day 7, up to 50% of renal γδ T cells produced IL-17A in situ and a large fraction of renal γδ T cells remained IL-17A
during chronic infection. Controlled depletion revealed that γδ T cells restricted renal
replication in the acute infection and provided protection during chronic renal infection and upon reinfection. Our results demonstrate that kidney-resident γδ T cells are nonredundant in limiting local
growth during chronic infection and provide enhanced protection against reinfection.
The present study examined the pathogenesis of interstitial inflammation and fibrosis in antihypertensively treated rats with two-kidney, one-clip hypertension. Hypertensive rats were randomized into ...four groups: no treatment and moderate, intermediate, and intensified lowering of blood pressure with increasing doses of a vasopeptidase inhibitor for 6 wk. The vasopeptidase inhibitor dose dependently lowered blood pressure. The tubulointerstitial damage was accompanied by a diffuse infiltration of mononuclear cells and circumscript mononuclear inflammatory cell cluster formation consisting mainly of T cells and to a lesser degree of macrophages and B cells. Real-time PCR analyses showed a dose-dependent induction of MCP-1 and the Th1-type chemokines IP10 and Mig as well as their receptor CXCR3 and the Th1 cytokine IFN-gamma. In situ hybridization and laser microdissection revealed a strong expression of these Th1-associated transcripts in the clusters and, in the case of MCP-1, also diffusely in the interstitium. The inflammation was accompanied by the appearance of myofibroblasts and synthesis of the fibrogenic factor plasminogen activator inhibitor-1 as well as the collagenase matrix metalloproteinase-2, leading to collagen I upregulation and interstitial scarring. No inflammation or fibrosis was found in normotensive rats treated with the vasopeptidase inhibitor. The renal injury in the clipped kidney is accompanied by compartment-specific chemokine expression and cell cluster formation of Th1 specificity associated with upregulation of fibrogenic proteins and matrix metalloproteinases. These findings suggest that the Th1 chemokines IP10 and Mig as well as their receptor CXCR3 are potential targets for therapeutic interventions in ischemic nephropathy.
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