Compartment specific expression of dendritic cell markers in human glomerulonephritis

Segerer, Stephan; Heller, F; Lindenmeyer, Maja T.; Schmid, Holger; Cohen, Clemens D.; Draganovici, Dan; Mandelbaum, Jana; Nelson, Peter J.; Gröne, Hermann–Josef; Gröne, Elisabeth F.; Figel, Ainhoa-M.; Nößner, Elfriede; Schlöndorff, Detlef

doi:10.1038/ki.2008.99

Cited by 119 publications

(142 citation statements)

References 55 publications

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“…In the glomerular compartment, few T cells, even fewer B cells and no dendritic cells are typically present. 29,46,47 Thus, macrophages, which we and others 48 could identify in glomeruli with lupus nephritis, may have a prominent role. Chang et al 9 show in vitro that BLyS stimulation of TACI expressing monocytes led to the enhancement of their survival and their activation.…”

Section: Discussionmentioning

confidence: 52%

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Intrarenal production of B-cell survival factors in human lupus nephritis

et al. 2011

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The B-cell survival factors APRIL and BLyS are important for B-cell maturation and activation and contribute to human autoimmune diseases. Interference with B-cell function by targeting these molecules is currently being investigated in large clinical trials for systemic lupus erythematosus. The local expression patterns of APRIL and BLyS have not been investigated in detail in kidneys with lupus nephritis. We studied the mRNA expression of APRIL, BLyS, and the corresponding receptors BCMA, TACI, and BAFF-R in microdissected human biopsies with proliferative lupus nephritis (n ¼ 25) and compared it with pretransplant biopsies of living donors (n ¼ 9). APRIL and BLyS mRNA levels were significantly higher in glomeruli of patients with proliferative lupus nephritis (12-and 30-fold, respectively). Tubulointerstitial expression of APRIL, BLyS, BCMA, and TACI was also significantly elevated. To localize the respective proteins in the kidney, APRIL, BLyS, and BAFF-R were studied by immunohistochemistry in renal biopsies with proliferative (n ¼ 21) or membranous (n ¼ 8) lupus nephritis. APRIL was prominently expressed in glomeruli with proliferative, but not membranous, lupus nephritis. The staining pattern was consistent with mesangial cells. A prominent accumulation of CD68-positive cells was present in glomeruli in association with APRIL expression. APRIL, BLyS, and BAFF-R were also expressed in interstitial inflammatory cell accumulation. This is the first study, which details local expression of APRIL and BLyS in glomeruli and tubulointerstitium of human proliferative lupus nephritis. This information might help define intrarenal effects of APRIL and BLyS inhibition in human lupus nephritis.

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Section: Discussionmentioning

confidence: 52%

“…The monoclonal mouse anti-CD68 antibody (Clone PG-M1, DAKO Germany, Hamburg) has previously been used extensively in formalin-fixed, paraffin-embedded renal biopsies. 29 Negative controls were performed on sections of allograft nephrectomies and human tonsils with a non-immune rabbit serum.…”

Section: Renal Biopsies and Immunohistochemistrymentioning

confidence: 99%

Intrarenal production of B-cell survival factors in human lupus nephritis

et al. 2011

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“…This is consistent with a recent report on human kidney. 48 We suspect the glomerular cells seen in the CX3CR1-GFP mice may represent other CX3CR1-expressing cells, such as NK cells, monocytes, or T cells. [51][52][53] Although a number of studies have documented changes in the numbers, trafficking, or maturation state of renal DCs in various pathophysiologic conditions, 47,54,55 the role of these renal DCs in their physiologic context remains poorly defined.…”

Section: Discussionmentioning

confidence: 99%

“…46 During renal injury, DCs are thought to contribute to renal inflammation and exacerbate kidney injury. 3,47,48 These studies were based on measures of DC infiltration and cytokine production but did not determine the functional relevance of DCs within their physiologic context in vivo. Contrary to these findings, our work used a conditional DC ablation model to demonstrate that resident renal DCs mediate protection in a nephrotoxic model of AKI.…”

Section: Discussionmentioning

confidence: 99%

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

Tadagavadi¹,

Reeves

2010

Journal of the American Society of Nephrology

139

161

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Inflammation contributes to the pathogenesis of acute kidney injury. Dendritic cells (DCs) are immune sentinels with the ability to induce immunity or tolerance, but whether they mediate acute kidney injury is unknown. Here, we studied the distribution of DCs within the kidney and the role of DCs in cisplatin-induced acute kidney injury using a mouse model in which DCs express both green fluorescence protein and the diphtheria toxin receptor. DCs were present throughout the tubulointerstitium but not in glomeruli. We used diphtheria toxin to deplete DCs to study their functional significance in cisplatin nephrotoxicity. Mice depleted of DCs before or coincident with cisplatin treatment but not at later stages experienced more severe renal dysfunction, tubular injury, neutrophil infiltration and greater mortality than nondepleted mice. We used bone marrow chimeric mice to confirm that the depletion of CD11c-expressing hematopoietic cells was responsible for the enhanced renal injury. Finally, mixed bone marrow chimeras demonstrated that the worsening of cisplatin nephrotoxicity in DC-depleted mice was not a result of the dying or dead DCs themselves. After cisplatin treatment, expression of MHC class II decreased and expression of inducible co-stimulator ligand increased on renal DCs. These data demonstrate that resident DCs reduce cisplatin nephrotoxicity and its associated inflammation.

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“…29 The primary antibody was a mouse anti-human CXCL12 (clone 79018, R&D Systems, Minneapolis, MN). Immunohistochemical analysis was performed on normal areas collected from TNs (n ϭ 3) and biopsy specimens from patients with NSC (n ϭ 3).…”

Section: Immunohistological Analysismentioning

confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

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In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

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Compartment specific expression of dendritic cell markers in human glomerulonephritis

Cited by 119 publications

References 55 publications

Intrarenal production of B-cell survival factors in human lupus nephritis

Intrarenal production of B-cell survival factors in human lupus nephritis

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

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