CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome

Vielhauer, Volker; Berning, Elias; Eis, Václav; Kretzler, Matthias; Segerer, Stephan; Strutz, Frank; Horuk, Richard; Gröne, Hermann Josef; Schlöndorff, Detlef; Anders, Hans‐Joachim

doi:10.1111/j.1523-1755.2004.66038.x

Cited by 140 publications

(104 citation statements)

References 31 publications

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“…Only a limited number of macrophages were observed in the tubulointerstitial space of the ADR-10d group, whereas at the end of the experiment a more prominent macrophage infiltration was observed, as also reported by Wang et al and Vielhauer et al 4,29 Pre-VPA treatment of ADR mice blocked the interstitial macrophage infil- …”

Section: Valproic Acid Hampers Renal Inflammationsupporting

confidence: 63%

“…In the ADR nephropathy model, fibrosis is accompanied by inflammation. 28,29 We show a reduction in inflammatory chemokines/cytokines and interstitial infiltrated macrophages in the ADR nephropathy model after VPA treatment. Less inflammation was also observed in the obstructive nephropathy model 12,13 and the autoimmune lupus model 17 after HDAC inhibition therapy.…”

Section: Discussionmentioning

confidence: 99%

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Valproic Acid Attenuates Proteinuria and Kidney Injury

Beneden

Geers

Pauwels

et al. 2011

Journal of the American Society of Nephrology

114

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Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD.

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Section: Valproic Acid Hampers Renal Inflammationsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Valproic Acid Attenuates Proteinuria and Kidney Injury

Beneden

Geers

Pauwels

et al. 2011

Journal of the American Society of Nephrology

114

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“…33 Moreover, we observed recently that in mice with focal-segmental glomerulosclerosis, improvement of tubulo-interstitial injury by drug treatment may occur while glomerular injury and proteinuria persist. 34 This further suggests independence of disease processes in the glomerulus from those occurring in the tubulo-interstitium.…”

Section: Discussionmentioning

confidence: 90%

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

et al. 2004

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Abstract-The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET A ) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET A receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by Ͼ50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21 Cip1/WAF1 . In vitro experiments blocking ET A receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury. Key Words: arterial presure Ⅲ nephrosclerosis Ⅲ DNA Ⅲ kidney failure Ⅲ renal artery Ⅲ expression Ⅲ kidney Ⅲ renal disease A ging represents an important factor determining onset and course of disease and has become a significant issue in view of the anticipated increase of the aging population. Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown. In otherwise healthy individuals Ն65 years of age, even in the absence of known risk factors such as hypertension or diabetes, glomerulosclerosis is frequently present. 3 Currently, Ϸ1.4% of the US total population is affected, and the incidence is expected to increase to Ͼ2% within the next 15 years. 3 Glomerulosclerosis and proteinuria involve injury of podocytes, also known as glomerular epithelial cells that maintain an intact filtration barrier and control glomerular basement membrane turnover under normal conditions. 4 -7 In addition to cell-specific changes during aging, cell c...

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“…Previous conclusions about the incidence of fibroblasts in the kidney on the basis of immunolabeling with anti-FSP1 (Chai et al 2003;Ito et al 2004;Iwano et al 2002;Okada et al 2000;Spurgeon et al 2004;Vielhauer et al 2004) or anti-S100A4 (Ito et al 2004;Basile et al 2005) must be reconsidered. The scarcity of FSP1-positive cells in the normal kidney has been interpreted as indication of a low incidence of fibroblasts (Iwano et al 2002;Okada et al 2000;Strutz and Neilson 2003).…”

Section: Discussionmentioning

confidence: 99%

Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys

Hir

Hegyi

Cueni-Loffing

et al. 2005

Histochem Cell Biol

117

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Fibrosis is considered as a central factor in the loss of renal function in chronic kidney diseases. The origin of fibroblasts and myofibroblasts that accumulate in the interstitium of the diseased kidney is still a matter of debate. It has been shown that accumulation of myofibroblasts in inflamed and fibrotic kidneys is associated with upregulation of fibroblast-specific protein 1 (FSP1, S100A4), not only in the renal interstitium but also in the injured renal epithelia. The tubular expression of FSP1 has been taken as evidence of myofibroblast formation by epithelial-mesenchymal transition (EMT). The identity of FSP1/S100A4 cells has not been defined in detail. We originally intended to use FSP1/ S100A4 as a marker of putative EMT in a model of distal tubular injury. However, since the immunoreactivity of FSP1 did not seem to fit with the distribution and shape of fibroblasts or myofibroblasts, we undertook the characterization of FSP1/S100A4-expressing cells in the interstitium of rodent kidneys. We performed immunolabeling for FSP1/S100A4 on thin cryostat sections of perfusion-fixed rat and mouse kidneys with peritubular inflammation, induced by thiazides and glomerulonephritis, respectively, in combination with ecto-5¢-nucleotidase (5¢NT), recognizing local cortical peritubular fibroblasts, with CD45, MHC class II, CD3, CD4 and Thy 1, recognizing mononuclear cells, with alpha smooth muscle actin (aSMA), as marker for myofibroblasts, and vimentin for intracellular intermediate filaments in cells of mesenchymal origin. In the healthy interstitium of rodents the rare FSP1/S100A4+ cells consistently co-expressed CD45 or lymphocyte surface molecules. Around the injured distal tubules of rats treated for 3-4 days with thiazides, FSP1+/ S100A4+, 5¢NT+, aSMA+, CD45+ and MHC class II+ cells accumulated. FSP1+/S100A4+ cells consistently co-expressed CD45. In the inflamed regions, aSMA was co-expressed by 5¢NT+ cells. In glomerulonephritic mice, FSP1+/S100A4+ cells co-expressed Thy 1, CD4 or CD3. Thus, in the inflamed interstitium around distal tubules of rats and of glomerulonephritic mice, the majority of FSP1+ cells express markers of mononuclear cells. Consequently, the usefulness of FSP1/S100A4 as a tool for detection of (myo)fibroblasts in inflamed kidneys and of EMT in vivo is put into question. In the given rat model the consistent coexpression of aSMA and 5¢NT suggests that myofibroblasts originate from resident peritubular fibroblasts.

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CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome

Cited by 140 publications

References 31 publications

Valproic Acid Attenuates Proteinuria and Kidney Injury

Valproic Acid Attenuates Proteinuria and Kidney Injury

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys

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