Progression of renal damage in human glomerulonephritides: Is there sleight of hand in winning the game?

Schena, Francesco Paolo; Gesualdo, Loreto; Grandaliano, Giuseppe; Montinaro, Vincenzo

doi:10.1038/ki.1997.475

Cited by 81 publications

(60 citation statements)

References 183 publications

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“…In the normal kidney, macrophages are mostly restricted to the renal capsule, pelvic wall, and adventitia of large vessels (34). However, in both inflammatory and noninflammatory renal disease, macrophage infiltration is a prominent feature (10,(35)(36)(37), where their cellular contents of reactive oxygen intermediates, proteases, inflammatory cytokines, and growth factors including TGF-␤ itself (10,35,38) are viewed as playing a significant role in mediating renal injury (35). Thus, the ability of tranilast to reduce macrophage accumulation, as noted in the present study, may potentially contribute to the observed attenuation of renal injury.…”

Section: Discussionmentioning

confidence: 99%

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Kelly

Zhang

Gow

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-␤ has been consistently implicated. anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-␤-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 ϫ/Ϭ 1.2 versus 20.5 ϫ/Ϭ 1.3 mg/d; P Ͻ 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P Ͻ 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-␤ activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-␤ signaling in vivo.In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.

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Section: Discussionmentioning

confidence: 99%

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Kelly

Zhang

Gow

et al. 2004

Journal of the American Society of Nephrology

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“…The interactions between inflammatory infiltrates and resident tubular cells contribute to ongoing inflammation, formation and activation of myofibroblasts, and ultimately interstitial fibrosis. The pivotal role of inflammatory infiltration in the progression of tubulointerstitial fibrosis is supported by the strict correlation between tubular atrophy, interstitial fibrosis, and the extent of interstitial infiltration (1,2).…”

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confidence: 99%

Oncostatin M, a Cytokine Released by Activated Mononuclear Cells, Induces Epithelial Cell-Myofibroblast Transdifferentiation via Jak/Stat Pathway Activation

Nightingale¹,

Patel²,

Suzuki³

et al. 2004

Journal of the American Society of Nephrology

111

137

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Abstract. Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithelial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofibroblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for ␣-smooth muscle actin, collagen I, and fibronectin EDA ϩ (markers for the myofibroblastic phenotype) were increased, whereas those for E-cadherin and cytokeratin 19 (markers for the epithelial phenotype) were decreased. cDNA microarray analysis was used to identify other changes in gene expression that might point to novel molecular mechanisms driving EMT. Of 1176 array genes, 61 demonstrated at least a twofold change at at least two consecutive time points, of the five time points examined (0.5, 4, 8, 16, and 48 h). Of these genes, 59% were upregulated and 41% were downregulated. The array indicated upregulation of expression of the oncostatin M (OSM)-specific receptor ␤ subunit from 4 to 48 h after exposure of kidney epithelial cells to activated PBMC conditioned medium, which contained high levels of OSM. In additional experiments, it was demonstrated that OSM induced EMT. OSM activated the Jak/Stat signaling pathway in epithelial cells, and a specific inhibitor of Jak2 blocked both its phosphorylation after exposure to OSM and the induction of ␣-actin and loss of cytokeratin 19 expression. Therefore, OSM is a novel inducer of EMT and is likely to be one of several cytokines produced by inflammatory infiltrates that contribute to this and subsequent tubulointerstitial fibrosis.

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“…A further reason for its importance is that ϳ25-50% of patients progress to end-stage kidney disease over 10 years (33). Thus MGN has a different and more progressive clinical course compared with the nonprogressive benign character of minimal-change nephrotic syndrome (33). HgCl 2 has been known to induce a systemic autoimmune disease, including membranous nephropathy with IgG deposits.…”

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confidence: 99%

Increased apical targeting of renal ENaC subunits and decreased expression of 11βHSD2 in HgCl₂-induced nephrotic syndrome in rats

Kim

Seigneux²,

Sassen³

et al. 2006

American Journal of Physiology-Renal Physiology

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Nielsen. Increased apical targeting of renal ENaC subunits and decreased expression of 11␤HSD2 in HgCl 2-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol 290: F674 -F687, 2006. First published September 27, 2005 doi:10.1152/ajprenal.00084.2005.-Nephrotic syndrome is often accompanied by sodium retention and generalized edema. We hypothesize that dysregulation of the epithelial sodium channel (ENaC) and/or of sodium (co)transporters may be responsible for the increased sodium retention associated with HgCl 2-induced nephropathy. In addition, we examined the hypothesis that the expression of type 2 11␤-hydroxysteroid dehydrogenase (11␤HSD2) is reduced, contributing to the enhanced mineralocorticoid activity. Membranous nephropathy was induced in Brown Norway rats by repeated injections of HgCl 2 (1 mg/kg sc), whereas the control group received only vehicle. After 13 days of treatment, the abundance of ENaC subunits, sodium (co)transporters, and 11␤HSD2 in the kidney was examined by immunoblotting and immunohistochemistry. HgCl 2 treatment induced marked proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and ascites. The protein abundance of ␣-ENaC was increased in the cortex/outer stripe of outer medulla (OSOM) and inner stripe of the outer medulla (ISOM). The protein abundances of ␤-ENaC and ␥-ENaC were decreased in the cortex/ OSOM while increased in the ISOM. Immunoperoxidase microscopy demonstrated increased targeting of ENaC subunits to the apical plasma membrane in the distal convoluted tubule, connecting tubule, and cortical and medullary collecting duct segments. Moreover, 11␤HSD2 abundance was decreased in cortex/OSOM and ISOM. The protein abundances of type 3 Na/H exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), and thiazide-sensitive Na-Cl cotransporter (NCC) were decreased. Moreover, the abundance of the ␣-1 subunit of the Na-K-ATPase was decreased in the cortex/OSOM and ISOM but remained unchanged in the inner medulla. These results suggest that increased apical targeting

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Progression of renal damage in human glomerulonephritides: Is there sleight of hand in winning the game?

Cited by 81 publications

References 183 publications

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Oncostatin M, a Cytokine Released by Activated Mononuclear Cells, Induces Epithelial Cell-Myofibroblast Transdifferentiation via Jak/Stat Pathway Activation

Increased apical targeting of renal ENaC subunits and decreased expression of 11βHSD2 in HgCl₂-induced nephrotic syndrome in rats

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Progression of renal damage in human glomerulonephritides: Is there sleight of hand in winning the game?

Cited by 81 publications

References 183 publications

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Oncostatin M, a Cytokine Released by Activated Mononuclear Cells, Induces Epithelial Cell-Myofibroblast Transdifferentiation via Jak/Stat Pathway Activation

Increased apical targeting of renal ENaC subunits and decreased expression of 11βHSD2 in HgCl2-induced nephrotic syndrome in rats

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Product

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Increased apical targeting of renal ENaC subunits and decreased expression of 11βHSD2 in HgCl₂-induced nephrotic syndrome in rats