Successful Treatment With Retinoids in Patients With Lupus Nephritis

Kinoshita, Koji; Kishimoto, Kazuya; Shimazu, Hideki; Nozaki, Yuji; Sugiyama, Masafumi; Ikoma, Shinya; Funauchi, Masanori

doi:10.1053/j.ajkd.2009.06.012

Cited by 45 publications

(47 citation statements)

References 18 publications

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“…Disease-, sex-, and time-dependent differences were identified. Using vitamin A as a potential intervention to reduce lupus nephritis (29)(30)(31)(32), we also showed that specific changes of the gut microbiota strongly correlated with disease attenuation. Predicted metagenomes associated with murine lupus and vitamin A treatments were also described.…”

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confidence: 72%

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Dynamics of Gut Microbiota in Autoimmune Lupus

Zhang

Liao

Sparks

et al. 2014

Appl Environ Microbiol

264

276

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Gut microbiota has been recognized as an important environmental factor in health, as well as in metabolic and immunological diseases, in which perturbation of the host gut microbiota is often observed in the diseased state. However, little is known on the role of gut microbiota in systemic lupus erythematosus. We investigated the effects of host genetics, sex, age, and dietary intervention on the gut microbiome in a murine lupus model. In young, female lupus-prone mice resembling women at childbearing age, a population with the highest risk for lupus, we found marked depletion of lactobacilli, and increases in Lachnospiraceae and overall diversity compared to age-matched healthy controls. The predicted metagenomic profile in lupus-prone mice showed a significant enrichment of bacterial motility-and sporulation-related pathways. Retinoic acid as a dietary intervention restored lactobacilli that were downregulated in lupus-prone mice, and this correlated with improved symptoms. The predicted metagenomes also showed that retinoic acid reversed many lupus-associated changes in microbial functions that deviated from the control. In addition, gut microbiota of lupus-prone mice were different between sexes, and an overrepresentation of Lachnospiraceae in females was associated with an earlier onset of and/or more severe lupus symptoms. Clostridiaceae and Lachnospiraceae, both harboring butyrate-producing genera, were more abundant in the gut of lupus-prone mice at specific time points during lupus progression. Together, our results demonstrate the dynamics of gut microbiota in murine lupus and provide evidence to suggest the use of probiotic lactobacilli and retinoic acid as dietary supplements to relieve inflammatory flares in lupus patients.

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confidence: 72%

“…Vitamin A has been shown to reduce lupus nephritis (29)(30)(31)(32). However, while orally administered vitamin A may come directly in contact with commensal bacteria in the intestinal tract during absorption, little is known about whether and how this nutrient affects gut microbiota.…”

Section: Lupus-associated Gut Microbial Composition and Diversitymentioning

confidence: 99%

Dynamics of Gut Microbiota in Autoimmune Lupus

Zhang

Liao

Sparks

et al. 2014

Appl Environ Microbiol

264

276

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“…26 In addition, treatment with RA reduced proteinuria in two patients with lupus nephritis. 27 However, how RA improves kidney disease remains mostly unclear. Our data suggest that RA is essential for appropriate differentiation of RPCs into podocytes and that this process is altered by albumin in a dose-dependent manner.…”

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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“…Interestingly, the effect of in vivo ATRA treatment on the development of lupus nephritis has already been tested in both mouse models (50,51) and humans (52). Long-term ATRA treatment in SLE-prone mice resulted in longer survival, significant reduction of proteinuria, renal pathological findings, and glomerular IgG deposits.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

Sarang

Joós

Garabuczi

et al. 2014

The Journal of Immunology

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Previous work in our laboratory has shown that transglutaminase 2 (TG2) acting as a coreceptor for integrin β3 is required for proper phagocytosis of apoptotic cells. In the absence of TG2, systemic lupus erythematosus–like autoimmunity develops in mice, similarly to other mice characterized by a deficiency in the clearance of apoptotic cells. In this study, we demonstrate that increasing TG2 expression alone in wild-type macrophages is not sufficient to enhance engulfment. However, during engulfment, the lipid content of the apoptotic cells triggers the lipid-sensing receptor liver X receptor (LXR), which in response upregulates the expression of the phagocytic receptor Mer tyrosine kinase and the phagocytosis-related ABCA1, and that of retinaldehyde dehydrogenases leading to the synthesis of a nonclassical retinoid. Based on our retinoid analysis, this compound might be a dihydro-retinoic acid derivative. The novel retinoid then contributes to the upregulation of further phagocytic receptors including TG2 by ligating retinoic acid receptors. Inhibition of retinoid synthesis prevents the enhanced phagocytic uptake induced by LXR ligation. Our data indicate that stimulation of LXR enhances the engulfment of apoptotic cells via regulating directly and indirectly the expression of a range of phagocytosis-related molecules, and its signaling pathway involves the synthesis of a nonclassical retinoid. We propose that retinoids could be used for enhancing the phagocytic capacity of macrophages in diseases such as systemic lupus erythematosus, where impaired phagocytosis of apoptotic cells plays a role in the pathogenesis of the disease.

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Successful Treatment With Retinoids in Patients With Lupus Nephritis

Cited by 45 publications

References 18 publications

Dynamics of Gut Microbiota in Autoimmune Lupus

Dynamics of Gut Microbiota in Autoimmune Lupus

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

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