All-trans-Retinoic Acid Inhibits the Development of Mesangial Proliferative Glomerulonephritis in Interleukin-6 Transgenic Mice

Shima, Yoshihito; Iwano, Masayuki; Yoshizaki, Kazuyuki; Tanaka, Toshio; Kawase, Ichiro; Nishimoto, Norihiro

doi:10.1159/000084655

Cited by 17 publications

(17 citation statements)

References 39 publications

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“…Studies in IL-6 transgenic mice suggested proliferative glomerulonephritis developed in the presence of high concentrations of IL-6 (23,25). The glomerulonephritis was inhibited by treatment with MR16-1 (anti-IL-6 receptor antibody), whose specificity to block IL-6 signaling was well-confirmed in the previous studies (12,26,27).…”

supporting

confidence: 57%

Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

Tomiyama-Hanayama¹,

Rakugi²,

Kohara³

et al. 2009

American Journal of Physiology-Renal Physiology

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T, Nishimoto N. Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice. Am J Physiol Renal Physiol 297: F679 -F684, 2009. First published July 1, 2009 doi:10.1152/ajprenal.90680.2008.-Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline-and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of salineand IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE Ϫ/Ϫ mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage. mesangial cells; macrophages; anti-mouse interleukin-6 receptor antibody MR16-1

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supporting

confidence: 57%

Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

Tomiyama-Hanayama¹,

Rakugi²,

Kohara³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…20 Interestingly, RA was previously found to provide protection in multiple experimental models of kidney disease, including mesangioproliferative GN, 21 puromycin-induced nephrosis, 22 lupus nephritis, 23 diabetic nephropathy, 24 and HIV nephropathy. 25 A recent study suggested that RA upregulates podocyte protein expression on parietal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

Peired¹,

Angelotti²,

Ronconi³

et al. 2013

Journal of the American Society of Nephrology

121

110

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In CKD, the risk of kidney failure and death depends on the severity of proteinuria, which correlates with the extent of podocyte loss and glomerular scarring. We investigated whether proteinuria contributes directly to progressive glomerulosclerosis through the suppression of podocyte regeneration and found that individual components of proteinuria exert distinct effects on renal progenitor survival and differentiation toward a podocyte lineage. In particular, albumin prevented podocyte differentiation from human renal progenitors in vitro by sequestering retinoic acid, thus impairing retinoic acid response element (RARE)-mediated transcription of podocyte-specific genes. In mice with Adriamycin nephropathy, a model of human FSGS, blocking endogenous retinoic acid synthesis increased proteinuria and exacerbated glomerulosclerosis. This effect was related to a reduction in podocyte number, as validated through genetic podocyte labeling in NPHS2.Cre;mT/mG transgenic mice. In RARE-lacZ transgenic mice, albuminuria reduced retinoic acid bioavailability and impaired RARE activation in renal progenitors, inhibiting their differentiation into podocytes. Treatment with retinoic acid restored RARE activity and induced the expression of podocyte markers in renal progenitors, decreasing proteinuria and increasing podocyte number, as demonstrated in serial biopsy specimens. These results suggest that albumin loss through the damaged filtration barrier impairs podocyte regeneration by sequestering retinoic acid and promotes the generation of FSGS lesions. Our findings may explain why reducing proteinuria delays CKD progression and provide a biologic rationale for the clinical use of pharmacologic modulators to induce regression of glomerular diseases.

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“…18,[35][36][37] Moreover, tRA, alone or in combination with low-dose immunosuppressive drugs, reduced lupus nephritis in both SLE mouse models and SLE patients. 17,18,36,38,39 Although the nephro-protective properties of tRA are well characterized, our recent findings demonstrate a paradoxical effect of tRA in MRL/Mp-Fas lpr (MRL/lpr) SLE mice. Surprisingly, the beneficial effects of tRA on glomerular injury and lymphadenopathy are counterbalanced by an exacerbation of disease severity in other lupus-affected organs.…”

Section: Introductionmentioning

confidence: 88%

All-Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL/lpr Mice

Theus

Sparks

Liao

et al. 2016

J Histochem Cytochem.

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Recently, we demonstrated that treatment with all- trans-retinoic acid (tRA) induced a paradoxical effect on immune activation during the development of autoimmune lupus. Here, we further describe its negative effects on mediating neuroinflammation and neurodegeneration. Female MRL/lpr mice were orally administered tRA or VARA (retinol mixed with 10% tRA) from 6 to 14 weeks of age. Both treatments had a significant effect on brain weight, which correlated with histopathological evidence of focal astrogliosis, meningitis, and ventriculitis. Infiltration of CD138- and Iba1-positve immune cells was observed in the third ventricle and meninges of treated mice that co-labeled with ICAM-1, indicating their inflammatory nature. Increased numbers of circulating plasma cells, autoantibodies, and total IgG were also apparent. IgG and C3 complement deposition in these brain regions were also prominent as was focal astrogliosis surrounding the ventricular lining and meninges. Using Fluoro-Jade staining, we further demonstrate that neuroinflammation was accompanied by neurodegeneration in the cortex of treated mice compared with vehicle controls. These findings indicate that vitamin A exposure exacerbates the immunogenic environment of the brain during the onset of systemic autoimmune disease. Vitamin A may therefore compromise the immuno-privileged nature of the central nervous system under a predisposed immunogenic environment.

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All-trans-Retinoic Acid Inhibits the Development of Mesangial Proliferative Glomerulonephritis in Interleukin-6 Transgenic Mice

Cited by 17 publications

References 39 publications

Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

All-Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL/lpr Mice

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