Long-lived plasma cells in the bone marrow produce memory antibodies that provide immune protection persisting for decades after infection or vaccination but can also contribute to autoimmune and allergic diseases. However, the composition of the microenvironmental niches that are important for the generation and maintenance of these cells is only poorly understood. Here, we demonstrate that, within the bone marrow, plasma cells interact with the platelet precursors (megakaryocytes), which produce the prominent plasma cell survival factors APRIL (a proliferation-inducing ligand) and IL-6 (interleukin-6). Accordingly, reduced numbers of immature and mature plasma cells are found in the bone marrow of mice deficient for the thrombopoietin receptor ( IntroductionAntibody-secreting plasma cells are found in many tissues. However, the plasma cells that provide antigen-specific systemic antibodies for up to decades after immunization or infection predominantly reside in the bone marrow. [1][2][3] There are multiple lines of evidence that individual plasma cells can survive in humans and mice for many months at the least. [4][5][6][7] These long-lived plasma cells are important for maintaining protective antibody memory. However, autoantibody-secreting long-lived plasma cells are refractory to conventional immunosuppressive therapy and therefore represent a therapeutic challenge in autoimmune diseases. [8][9][10] Plasma cell survival is not cell-autonomous but depends on signals provided by their environment. The most potent plasma cell survival factors identified so far are a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF-␣), stromal-derived factor-1␣, and signals transduced via CD44. [11][12][13][14] The bone marrow contains multiple microenvironmental niches that stimulate cellular proliferation, differentiation, and survival. [15][16][17][18][19][20] Each niche seems to support specifically one or a few particular hematopoietic stem or precursor cells. In this way, the sizes of these populations are limited by the number of available niches. 16,21 Similarly, competition for a limited number of survival niches may also control the turnover rate within the bone marrow plasma cell compartment. 12,[22][23][24] One or multiple niches may exist that have the capability to support the terminal differentiation and survival of bone marrow plasma cells. 25 As indicated by strong colocalization between a particular subtype of stromal-derived factor-1␣ ϩ reticular stromal cells and immunoglobulin G ϩ (IgG ϩ ) bone marrow plasma cells, the former seems to be an important element of plasma cell niches in that tissue. 26 However, in culture, bone marrow stromal cells support plasma cell survival only for a limited time, 13 suggesting that additional cell types contribute to the formation of plasma cell niches.In addition, it has been shown that macrophage-derived APRIL is required to support differentiation/survival of bone marrow plasma cells during early life, suggesting that factors ...

The existence of a local renin angiotensin system (RAS) of the kidney has been established. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and high concentrations of luminal angiotensin II have been found in the proximal tubule. Although functional data have documented the relevance of a local RAS, the dualism between biosynthesis and endocytotic uptake of its components and their cellular processing has been incompletely understood. To resolve this, we have selectively analyzed their distribution, endocytosis, transcytosis, and biosynthesis in the proximal tubule. The presence of immunoreactive AGT, restricted to the early proximal tubule, was due to its retrieval from the ultrafiltrate and storage in endosomal and lysosomal compartments. Cellular uptake was demonstrated by autoradiography of radiolabeled AGT and depended on intact endocytosis. AGT was identified as a ligand of the multiple ligandbinding repeats of megalin. AGT biosynthesis was restricted to the proximal straight tubule, revealing substantial AGT mRNA expression. Transgenic AGT overexpression under the control of an endogenous promoter was also restricted to the late proximal tubule. Proximal handling of renin largely followed the patterns of AGT, whereas its local biosynthesis was not significant. Transcytotic transport of AGT in a proximal cell line revealed a 5% recovery rate after 1 h. ACE was expressed along late proximal brush-border membrane, whereas ACE2 was present along the entire segment. Surface expression of ACE and ACE2 differed as a function of endocytosis. Our data on the localization and cellular processing of RAS components provide new aspects of the functional concept of a "self-contained" renal RAS.

Patients with proteinuric kidney diseases often experience symptoms of salt and water retention. It has been hypothesized that the dysregulated Na+ absorption is due to increased proteolytic cleavage of epithelial sodium channel (ENaC) and increased Na,K-ATPase expression. Microarray analysis identified a reduced corin mRNA expression in kidneys from rat models of puromycin aminonucleoside-induced nephrotic syndrome (PAN) and acute anti-Thy1 glomerulonephritis (GN). Corin has been shown to convert pro-atrial natriuretic peptide (ANP) to ANP. Because ANP resistance has been assumed to be a mechanism accounting for volume retention, experiments were undertaken to analyze the renal expression and function of corin. Immunohistochemistry revealed that corin co-localized with ANP. In PAN and GN, kidneys exhibited concomitant increased pro-ANP and decreased ANP protein expression levels consistent with low corin levels. Importantly, kidneys from corin −/− mice showed increased levels of renal β-ENaC, phosphodiesterase 5 (PDE5) and protein kinase G II (PKGII) when compared to wild-type mice. Similar expression profile was observed in cell culture experiments suggesting that the increase in PDE5 and PKGII could account for the increase in β-ENaC as observed in PAN and GN. To conclude, our data provide novel insights into the mechanisms of volume retention in renal disease with corin as an important new mediator that acts through PKGII induction and ENaC activation.

Our results demonstrate that an activation of the renal urine concentrating mechanism by desmopressin causes renal medullary hypoxia and an upregulation of hypoxia-inducible gene expression.

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