tretinoin and Glomerulonephritis

The association of glomerulonephritis and malignant hematological disease is uncommon, but well known in chronic leukemias, lymphomas, and monoclonal gammopathies. However, only a few cases of glomerulonephritis and acute myeloid leukemia have been reported in the literature. We describe the first case of a genetically diagnosed acute promyelocytic leukemia presenting with nephrotic range proteinuria that resolved with induction therapy with ATRA and ATO and performed a comprehensive review of the literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Glomerulonephritis; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

We previously showed that all-

Topics: Animals; Bacterial Translocation; Contraindications, Drug; Dendritic Cells; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Drug Synergism; Dysbiosis; Female; Gastrointestinal Microbiome; Gene Expression Regulation; Glomerulonephritis; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; RNA; RNA-Seq; Specific Pathogen-Free Organisms; Spleen; Terpenes; Tretinoin; Vitamin A

Proliferation of glomerular epithelial cells, including podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum-induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wild-type mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wild-type mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wild-type mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to the coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells toward a podocyte phenotype. In vitro, RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.

Topics: Animals; Autoantibodies; Biomarkers; Biopsy; Bowman Capsule; Cell Proliferation; Cell Transdifferentiation; Cells, Cultured; Glomerulonephritis; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Podocytes; Protective Agents; Retinoic Acid Receptor alpha; Tretinoin

All-trans retinoic acid (ATRA), a promising therapeutic agent, has been confirmed in animal experiments as playing a protective role against renal diseases. The renin-angiotensin aldosterone system (RAAS) plays a key role in the pathogenesis of renal diseases, and RAAS inhibitors can prevent the progression of kidney diseases. In our previous study, we found that ATRA could play a protective role against glomerulosclerosis (GS) lesions in rats, and its effect was similar to RAAS inhibitors. However, whether ATRA treatment was associated with RAAS expression was not clear.. Six-week-old male Wistar rats were divided into three groups: sham operation group (SHO), glomerulosclerosis model group without treatment (GS) and GS model group treated with ATRA (GA). At the end of 13 weeks, the relevant samples were collected and analyzed.. The mRNA and protein expression of angiotensin-converting enzyme 1 (ACE1) in the GS group was notably higher when compared with the SHO group. However, mRNA and protein expression of ACE1 in the ATRA treatment group was markedly down-regulated when compared with the GS group. Angiotensin-converting enzyme 2 (ACE2) expression (mRNA or protein) in the GS group was reduced compared with that in the SHO group, and ATRA markedly increased the mRNA and protein expression of ACE2 compared with the GS group. The levels of protein expression of angiotensin I and angiotensin II were significantly up-regulated in the GS group compared with those in the SHO group, and ATRA reduced their expression in the GA group when compared with the GS group.. ATRA is associated with RAAS expression in GS rats, but its detailed mechanism needs to be elucidated by further research.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Collagen Type IV; Fibronectins; Glomerulonephritis; Immunohistochemistry; Kidney Glomerulus; Male; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tretinoin

All-trans-retinoic acid (ATRA), a vitamin A derivative, was reported to suppress the interleukin-6 (IL-6) production and to downregulate the IL-6 receptor (IL-6R) and/or its signal transducer glycoprotein 130. We investigated the in vivo antinephritic effect of ATRA on IL-6 transgenic mice which had developed mesangial proliferative glomerulonephritis (PGN) as well as its in vitro inhibitory effect on the proliferation of rat mesangial cells. In vivo experiments on IL-6 transgenic mice showed that ATRA administration suppressed proteinuria and hematuria and reduced the IL-6 concentrations; furthermore, histological examination demonstrated that it improved PGN. In vitro experiments using rat mesangial cells demonstrated that ATRA inhibited cell growth in a dose-dependent manner within a range from 10(-4) to 10(-6) M. This inhibition by ATRA was partially counteracted by the addition of IL-6. RT-PCR assay results showed that ATRA also reduced IL-6R, but not the glycoprotein 130 expression in mesangial cells. These findings indicate that, by blocking of the IL-6 function, ATRA may be therapeutically effective in PGN.

Topics: Animals; Antineoplastic Agents; Cell Culture Techniques; Cell Proliferation; Cytokine Receptor gp130; Dose-Response Relationship, Drug; Down-Regulation; Glomerulonephritis; Hematuria; Interleukin-6; Mice; Mice, Transgenic; Proteinuria; Rats; Receptors, Interleukin-6; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin

Podocytes are terminally differentiated and highly specialized epithelial cells. The factors governing podocyte differentiation are poorly understood. We tested the hypothesis that all-trans retinoic acid (ATRA), a vitamin A derivative, induces podocyte differentiation in vitro and in vivo.. We tested the effects of ATRA on podocytes. Primary rat, primary mouse, and immortalized mouse podocytes were exposed to ATRA (1, 5, 10, 20, 40, 50, 80, 160, and 200 micromol/L) or control (ethanol) for 72 hours. Cell morphology was examined by electron microscopy, the expression of podocyte specific proteins was measured by immunoflourescence and Western blot analysis, cell number and apoptosis were measured by 3-[4,5] dimethylthiazol-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst staining, respectively. To determine if ATRA alters podocyte differentiation in vivo, experimental injury was induced in C57BL6 mice using the antiglomerular antibody. Animals were given either daily intraperitoneal ATRA (16 mg/kg) or vehicle (corn oil). For end points, we measured proteinuria, podocyte-specific protein immunostaining, and proliferation [proliferating cell nuclear antigen (PCNA)] at days 5 and 14 (N= 5/group/time point).. ATRA induced podocyte process formation in vitro, and significantly increased the expression of nephrin and podocin. This coincided with a reduction in proliferation. ATRA also significantly prevented the decrease in staining for synaptopodin, nephrin, and podocin in experimental animals (P < 0.05 vs. control). This was accompanied by reduced proteinuria and decreased podocyte proliferation (P < 0.05 vs. control).. ATRA induces podocyte differentiation in vitro and in vivo and alters the expression of certain podocyte-specific proteins. Further studies are ongoing to delineate the mechanism of this effect.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Cell Division; Cell Line, Transformed; Glomerulonephritis; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Proteinuria; Rats; Rats, Sprague-Dawley; Tretinoin

Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F(1) (NZB/W F(1)) mice. Three-month-old NZB/W F(1) mice were separated into two groups: one treated with all-trans-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-gamma, IL-2, and IL-10 in splenic CD4(+) T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F(1) mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.

Topics: Animals; Antibodies, Antinuclear; CD4-Positive T-Lymphocytes; Crosses, Genetic; Cytokines; Glomerulonephritis; Immunoglobulins; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred NZB; Proteinuria; RNA, Messenger; Splenomegaly; Survival Rate; Tretinoin

Transforming growth factor-beta1 (TGF-beta 1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-beta system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n = 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8), i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-beta 1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P < 0.025). The increase of cortical TGF-beta 1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P < 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P < 0.05). In all-trans retinoic acid-treated animals with Thy-GN, the increase of glomerular TGF-beta 1 protein (P < 0.008) and TGF-beta 1 (P < 0.025) and TGF receptor II mRNA (P < 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-beta 1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-beta 1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P < 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-beta 1 and TGF receptor II expression.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Extracellular Matrix; Gene Expression; Glomerulonephritis; Isotretinoin; Kidney Cortex; Kidney Glomerulus; Male; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Systole; Thy-1 Antigens; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tretinoin

Sustained high output release of Nitric oxide (NO) as result of activation of inducible nitric oxide synthase (iNOS), and increased production of the antiproliferative/profibrotic cytokine transforming growth factor-beta1 (TGF-beta1) are well documented in glomerulonephritis. Modulation of iNOS activity and of TGF-beta1 production can therefore be viewed as anti-inflammatory strategies. The present study employed all-trans retinoic acid (atRA) which is known to have anti-inflammatory effects and to modulate expression of iNOS and TGF-beta1, in order to explore its effect on iNOS enzyme activity and TGF-beta1 production in anti-GBM antibody induced glomerulonephritis. Glomerulonephritis was induced in Lewis rats by injection of anti-GBM antibody. A group of nephritic rats were given daily administration of atRA for 14-16 days. Extent of proteinuria was assessed by measuring urine protein and creatinine excretion. iNOS enzyme activity was measured by calculating conversion of L[14C]arginine to L-[14C]citrulline in glomerular protein lysates. Levels of TGF-beta1 in glomerular protein lysates were measured by quantitative ELISA. Levels of proliferating nuclear antigen (PCNA), TGF-beta receptor II (TGFbeta-RII), and fibronectin were assessed by Western blot analysis. Glomerular iNOS activity in atRA treated nephritic animals was attenuated in comparison to that in nephritic controls that were not. Glomerular expression of PCNA was also reduced. Levels of TGF-beta1 were increased in glomeruli of atRA treated nephritic animals. In these animals, there was no change in glomerular levels of TGF-beta receptor II (TGFbeta-RII) or fibronectin. and there was no reduction in urine protein excretion. These results suggest that atRA attenuates iNOS activity and proliferation in glomeruli of nephritic animals. The failure of atRA treatment to reduce proteinuria could be due to the increase in TGF-beta1 levels and to inhibition of iNOS-driven NO production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies; Autoantibodies; Cell Division; Disease Models, Animal; Glomerulonephritis; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Proliferating Cell Nuclear Antigen; Proteinuria; Rats; Rats, Inbred Lew; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tretinoin

Nitric oxide (NO) release as a result of cytokine-mediated activation of inducible nitric oxide synthase (iNOS) in mesangial cells can be sustained and lead to oxidative injury in various forms of glomerular inflammation. Inhibition of iNOS expression and/or activity could therefore be an effective anti-inflammatory strategy. The present study was undertaken to explore whether retinoids, which are known to have anti-inflammatory and immuno-modulatory actions, can attenuate cytokine-stimulated iNOS expression and enzyme activity in murine mesangial cells.. Expression of iNOS was evaluated by NO production (nitrite analysis), protein (Western blot analysis) and mRNA (RT-PCR analysis) levels in mesangial cells stimulated by a combination of lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in the presence and absence of all-trans-retinoic acid (ATRA) or its active metabolite, 13-cis-retinoic acid (13-cis-RA). Changes in iNOS enzyme activity were assessed by calculating conversion of L-[14C]arginine to L-[14C]citrulline. The levels of transcription factors nuclear factor-kappaB (NF-kappaB) and activated protein-1 (AP-1) in nuclear extracts prepared from mesangial cells stimulated by a combination of LPS and IFN-gamma in the presence and absence of ATRA was assessed by immunoblot analysis. The effect of both retinoids on transforming growth factor-beta1 (TGF-beta1) levels was also assessed by a quantitative enzyme immunoassay method.. The combination of LPS/IFN-gamma stimulated NO production, induced iNOS expression (mRNA and protein) and increased iNOS enzyme activity. ATRA and 13-cis-RA dose-dependently attenuated NO production. This effect was most pronounced at ATRA concentration of 10 microM. At this concentration, ATRA attenuated iNOS expression (mRNA and protein levels) and enzyme activity. ATRA also reduced nuclear levels of both subunits (p50 and p65) of NF-kappaB. TGF-beta1 levels in mesangial cells stimulated with LPS/IFN-gamma in presence of ATRA or 13-cis-RA were also reduced indicating that TGF-beta1 did not mediate the suppressive effect of retinoids on iNOS.. Our studies demonstrate that the retinoids ATRA and 13-cis-RA attenuate iNOS expression and activity in cytokine-stimulated murine mesangial cells. These retinoids may emerge as naturally occurring compounds for treatment of inflammatory glomerular diseases.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cell Line, Transformed; Gene Expression Regulation, Enzymologic; Glomerular Mesangium; Glomerulonephritis; Interferon-gamma; Isotretinoin; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-fos; RNA, Messenger; Teratogens; Transcription Factor AP-1; Transforming Growth Factor beta; Tretinoin