scholarly journals Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

2020 ◽  
Vol 21 (20) ◽  
pp. 7495
Author(s):  
Kentaro Terai ◽  
Denan Jin ◽  
Kenji Watase ◽  
Akihisa Imagawa ◽  
Shinji Takai
Keyword(s):  
Oxidative Stress ◽  
Transforming Growth Factor ◽  
Fasting Blood Glucose ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Oxidative Stress Marker ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Nadph Oxidase 4 ◽  
Significant Difference

Chymase has several functions, such as angiotensin II formation, which can promote diabetic kidney disease (DKD). In this study, we evaluated the effect of the chymase inhibitor TY-51469 on DKD in diabetic db/db mice. Diabetic mice were administered TY-51469 (10 mg/kg/day) or placebo for 4 weeks. No significant difference was observed in body weight and fasting blood glucose between TY-51469- and placebo-treated groups. However, a significant reduction in urinary albumin/creatinine ratio was observed in the TY-51469-treated group compared with the placebo-treated group. In the renal extract, chymase activity was significantly higher in placebo-treated mice than in non-diabetic db/m mice, but it was reduced by treatment with TY-51469. Both NADPH oxidase 4 expression and the oxidative stress marker malondialdehyde were significantly augmented in the placebo-treated group, but they were attenuated in the TY-51469-treated group. Significant increases of tumor necrosis factor-α and transforming growth factor-β mRNA levels in the placebo-treated group were significantly reduced by treatment with TY-51469. Furthermore, the expression of nephrin, which is a podocyte-specific protein, was significantly reduced in the placebo-treated group, but it was restored in the TY-51469-treated group. These findings demonstrated that chymase inhibition reduced albuminuria via attenuation of podocyte injury by oxidative stress.

Antagonistic Effects of Insulin and TGF-β3 during Chondrogenic Differentiation of Human BMSCs under a Minimal Amount of Factors

2016 ◽  
Vol 201 (2) ◽  
pp. 88-96 ◽  
Author(s):  
Emilio Satoshi Hara ◽  
Mitsuaki Ono ◽  
Yuya Yoshioka ◽  
Junji Ueda ◽  
Yuri Hazehara ◽  
...  
Keyword(s):  
Chondrogenic Differentiation ◽  
Transforming Growth Factor ◽  
Direct Interaction ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Minimal Amount ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Antagonistic Effects

Growth factors are crucial regulators of cell differentiation towards tissue and organ development. Insulin and transforming growth factor-β (TGF-β) have been used as the major factors for chondrogenesis in vitro, by activating the AKT and Smad signaling pathways. Previous reports demonstrated that AKT and Smad3 have a direct interaction that results in the inhibition of TGF-β-mediated cellular responses. However, the result of this interaction between AKT and Smad3 during the chondrogenesis of human bone marrow-derived stem/progenitor cells (hBMSCs) is unknown. In this study, we performed functional analyses by inducing hBMSCs into chondrogenesis with insulin, TGF-β3 or in combination, and found that TGF-β3, when applied concomitantly with insulin, significantly decreases an insulin-induced increase in mRNA levels of the master regulator of chondrogenesis, SOX9, as well as the regulators of the 2 major chondrocyte markers, ACAN and COL2A1. Similarly, the insulin/TGF-β3-treated group presented a significant decrease in the deposition of cartilage matrix as detected by safranin O staining of histological sections of hBMSC micromass cultures when compared to the group stimulated with insulin alone. Intracellular analysis revealed that insulin-induced activation of AKT suppressed Smad3 activation in a dose-dependent manner. Accordingly, insulin/TGF-β3 significantly decreased the TGF-β3-induced increase in mRNA levels of the direct downstream factor of TGF-β/Smad3, CCN2/CGTF, compared to the group stimulated with TGF-β3 alone. On the other hand, insulin/TGF-β3 stimulation did not suppress insulin-induced expression of the downstream targets TSC2 and DDIT4/REDD1. In summary, insulin and TGF-β3 have antagonistic effects when applied concomitantly, with a minimal number of factors. The application of an insulin/TGF-β3 combination without further supplementation should be used with caution in the chondrogenic differentiation of hBMSCs.

scholarly journals Granulosal and thecal expression of bone morphogenetic protein- and activin-binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro

Reproduction ◽  
2011 ◽  
Vol 142 (4) ◽  
pp. 581-591 ◽  
Author(s):  
Claire Glister ◽  
Leanne Satchell ◽  
Phil G Knight
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Mrna Level ◽  
Transcript Abundance ◽  
Transforming Growth Factor Β ◽  
Follicle Development ◽  
Mrna Levels ◽  
Theca Interna

Evidence supports local roles for transforming growth factor β superfamily members including activins and bone morphogenetic proteins (BMP) in follicle development. Access of these ligands to signalling receptors is likely modulated by extracellular binding proteins (BP). In this study, we comparedex vivoexpression of four BPs (chordin, gremlin, noggin and follistatin) in granulosal (GC) and theca interna (TC) compartments of developing bovine antral follicles (1–18 mm). Effects of FSH and IGF on BMP and BP expression by cultured GC, and effects of LH and BMPs on BP expression by cultured TC were also examined. Follicular expression of all four BP transcripts was higher in GC than TC compartments (P<0.001) a finding confirmed by immunohistochemistry. Follicle category affected (P<0.01) gremlin and follistatin mRNA abundance, with a significant cell-type×follicle category interaction for chordin, follistatin and noggin. Noggin transcript abundance was lower (P<0.05) in GC of large ‘E-active’ than ‘E-inactive’ follicles while follistatin mRNA level was higher (P<0.01). FSH enhanced CYP19, FSHR, INHBA and follistatin by GC without affecting BMP or BMP–BP expression. IGF increased CYP19 and follistatin, reduced BMP4, noggin and gremlin but did not affect chordin orFSHRmRNA levels. LH increased TC androgen secretion but had no effect on BMP or BP expression. BMPs uniformly suppressed TC androgen production whilst increasing chordin, noggin and gremlin mRNA levels up to 20-fold (P<0.01). These findings support the hypothesis that extracellular BP, mostly from GC, contribute to the regulation of intrafollicular BMP/activin signalling. Enhancement of thecal BP expression by BMP implies an autoregulatory feedback role to prevent excessive signalling.

Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes

2012 ◽  
Vol 124 (3) ◽  
pp. 191-202 ◽  
Author(s):  
Mona Sedeek ◽  
Alex Gutsol ◽  
Augusto C. Montezano ◽  
Dylan Burger ◽  
Aurelie Nguyen Dinh Cat ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Disease Process ◽  
Thiobarbituric Acid ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
High Dose ◽  
Diabetic Mice ◽  
Mitogen Activated Protein

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.

Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

2007 ◽  
Vol 67 (4) ◽  
pp. 559-562 ◽  
Author(s):  
K Warstat ◽  
T Pap ◽  
G Klein ◽  
S Gay ◽  
W K Aicher
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Synovial Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
The Matrix ◽  
Specific Tissue ◽  
Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

scholarly journals Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis

2014 ◽  
Vol 25 (8) ◽  
pp. 1234-1243 ◽  
Author(s):  
Shan Cao ◽  
Lan Xiao ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Responses ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Regulatory Factor ◽  
Epithelial Homeostasis ◽  
Repressive Effect ◽  
Single Binding Site

Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide variety of cellular responses, but the exact mechanisms that control Smurf2 abundance are largely unknown. Here we identify microRNA-322 (miR-322) and miR-503 as novel factors that regulate Smurf2 expression posttranscriptionally. Both miR-322 and miR-503 interact with Smurf2 mRNA via its 3′-untranslated region (UTR) and repress Smurf2 translation but do not affect total Smurf2 mRNA levels. Studies using heterologous reporter constructs reveal a greater repressive effect of miR-322/503 through a single binding site in the Smurf2 3′-UTR, whereas point mutation of this site prevents miR-322/503–induced repression of Smurf2 translation. Increased levels of endogenous Smurf2 via antagonism of miR-322/503 inhibits TGF-β–induced Smad2 activation by increasing degradation of phosphorylated Smad2. Furthermore, the increase in Smurf2 in intestinal epithelial cells (IECs) expressing lower levels of miR-322/503 is associated with increased resistance to apoptosis, which is abolished by Smurf2 silencing. These findings indicate that miR-322/503 represses Smurf2 translation, in turn affecting intestinal epithelial homeostasis by altering TGF-β/Smad2 signaling and IEC apoptosis.

scholarly journals The expression of transforming growth factor β in pregnant rat myometrium is hormone and stretch dependent

Reproduction ◽  
2007 ◽  
Vol 134 (3) ◽  
pp. 503-511 ◽  
Author(s):  
Oksana Shynlova ◽  
Prudence Tsui ◽  
Anna Dorogin ◽  
B Lowell Langille ◽  
Stephen J Lye
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Late Gestation ◽  
Quiescent State ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Threefold Increase ◽  
Antagonist Ru486

From a quiescent state in early pregnancy to a highly contractile state in labor, the myometrium displays tremendous growth and remodeling. We hypothesize that the transforming growth factor β (TGFβ) system is involved in the differentiation of pregnant myometrium throughout gestation and labor. Furthermore, we propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial TGFβs. The expression of TGFβ1-3 mRNAs and proteins was examined by real-time PCR, Western immunoblot, and localized with immunohistochemistry in the rat uterus throughout pregnancy and labor. Tgfβ1-3 genes were expressed differentially in pregnant myometrium. Tgfβ2 gene was not affected by pregnancy, whereas the Tgfβ1 gene showed a threefold increase during the second half of gestation. In contrast, we observed a dramatic bimodal change in Tgfβ3 gene expression throughout pregnancy. Tgfβ3 mRNA levels first transiently increased at mid-gestation (11-fold on day 14) and later at term (45-fold at labor, day 23). Protein expression levels paralleled the changes in mRNA. Treatment of pregnant rats with the progesterone (P4) receptor antagonist RU486 induced premature labor on day 19 and increased Tgfβ3 mRNA, whereas artificial maintenance of elevated P4 levels at late gestation (days 20–23) caused a significant decrease in the expression of Tgfβ3 gene. In addition, Tgfβ3 was up-regulated specifically in the gravid horn of unilaterally pregnant rats subjected to a passive biological stretch imposed by the growing fetuses, but not in the empty horn. Collectively, these data indicate that the TGFβ family contributes in the regulation of myometrial activation at term integrating mechanical and endocrine signals for successful labor contraction.

Abstract 297: Cardiac Transforming-growth-factor β-stimulated Clone 22 Gene Expression By Hypertrophic Stimuli

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Annina Kelloniemi ◽  
Jani Aro ◽  
Elina Koivisto ◽  
Heikki Ruskoaho ◽  
Jaana Rysä
Keyword(s):  
Growth Factor ◽  
Gene Transfer ◽  
Transforming Growth Factor ◽  
Pressure Overload ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Ang Ii ◽  
Sd Rats

Objectives: Transforming-growth-factor β-stimulated clone 22 (TSC-22) is a leucine zipper protein expressed in many tissues and possessing various transcription-modulating activities. However, its function in the heart remains largely unknown. The aim of the present study was to characterize the cardiac TSC-22 expression. Methods: Acute pressure overload was accomplished in conscious Sprague-Dawley (SD) rats by intravenous infusion of arginine 8 -vasopressin (AVP, 0.05 μg/kg/min) for 4 hours and subcutaneous infusion of angiotensin II (Ang II, 33 μg/kg/h) with and without Ang II receptor type 1 blocker losartan (400 μg/kg/h) by using osmotic minipumps for 2 weeks. Adenovirus-mediated intramyocardial gene transfer of TSC-22 was performed into left ventricle (LV) of SD rats. Experimental myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Cultured neonatal rat ventricular myocytes (NRVM) were treated with endothelin-1 (ET-1, 100 nM). Results: A significant 1.6-fold increase ( P <0.05) in LV TSC-22 mRNA levels was noted already after 1 hour AVP infusion. Moreover, Ang II infusion markedly upregulated TSC-22 expression, LV mRNA levels being highest at 6 hours (11-fold, P <0.001). Simultaneous infusion of losartan completely abolished Ang II-induced increase in TSC-22 mRNA levels. Adenovirus-mediated gene transfer of TSC-22 into LV resulted a 1.9-fold ( P <0.001) increase in TSC-22 mRNA levels, accompanied by upregulated BNP mRNA levels (1.4-fold, P <0.01). In response to experimental MI, TSC-22 mRNA levels were elevated 4.1-fold ( P <0.001) at 1 day and 1.9-fold ( P <0.05) at 4 weeks. In cultured NRVM, ET-1 treatment increased TSC-22 mRNA levels from 1 h to 24 h, the greatest increase being observed at 12 h (2.7-fold, P <0.001). TSC-22 protein levels were upregulated from 4 h to 24 h with the highest increase at 24 h (4.7-fold, P <0.01). Conclusion: These results indicate that TSC-22 expression is rapidly activated in response to pressure overload, MI and in ET-1 treated cultured NRVM. Moreover, adenovirus-mediated overexpression of TSC-22 mRNA was associated with elevated left ventricular BNP mRNA levels.

scholarly journals P1196AN INIHIBITOR OF KRUPPEL-LIKE FACTOR 5 SUPPRESSES PERITONEAL FIBROSIS IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Kumiko Muta ◽  
Yuka Nakazawa ◽  
Yoko Obata ◽  
Hiro Inoue ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Peritoneal Fibrosis ◽  
Retinoic Acid Receptor Α ◽  
Klf5 Expression

Abstract Background and Aims We presented previously that Am80, a synthetic retinoic acid receptor α specific agonist, inhibited the expression of Krüppel-like transcription factor 5 (KLF5) and reduced peritoneal fibrosis in mice. Now, we examined further detail about the mechanism to inhibit peritoneal fibrosis. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) into peritoneal cavity of ICR mice. Am80 was administered orally for every day from the start of CG injection. After 3 weeks of treatment, peritoneal tissues were examined using serial sections by immunohistochemistry to identify what kind of cells expressed KLF5. We also examined the effect of Am80 to inhibit peritoneal fibrosis in vitro. Results While KLF5 was expressed in the thickened submesothelial area of CG injected mice, Am80 treatment reduced KLF5 expression and remarkably attenuated peritoneal thickening. The numbers of transforming growth factor β positive cells, α-smooth muscle actin (αSMA) or F4/80 positive cells were significantly decreased in Am80 treated group. KLF5 was expressed in αSMA, F4/80 or CD31 positive cells. Conclusion These results indicate the KLF5 might not only associate phenotypical differentiation from fibroblasts to myofibroblasts but also regulate inflammatory responses and angiogenesis in peritoneal fibrosis model. Am80 can suppress peritoneal fibrosis through inhibiting these mechanisms. In vitro experiments are ongoing.

scholarly journals Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice

2016 ◽  
Vol 310 (7) ◽  
pp. G526-G538 ◽  
Author(s):  
Jelske N. van der Veen ◽  
Susanne Lingrell ◽  
Xia Gao ◽  
Ariel D. Quiroga ◽  
Abhijit Takawale ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Transforming Growth Factor ◽  
Body Weight Gain ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Liver Weight ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Important Enzyme

Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt−/− mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt+/+ and Pemt−/− mice were fed a HFD with or without pioglitazone (20 mg·kg−1·day−1) for 10 wk. Pemt−/− mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt−/− mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt−/− mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt−/− mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt−/− mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 ( Col1a1), tissue inhibitor of metalloproteinases 1 ( Timp1), α-smooth muscle actin ( Acta2), and transforming growth factor-β ( Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt−/− mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt −/− mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance.

The anemia of the newborn induces erythropoietin expression in the developing mouse retina

2010 ◽  
Vol 299 (1) ◽  
pp. R111-R118 ◽  
Author(s):  
N. Scheerer ◽  
N. Dünker ◽  
S. Imagawa ◽  
M. Yamamoto ◽  
N. Suzuki ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Ganglion Cells ◽  
Retinal Development ◽  
Transforming Growth Factor Β ◽  
Neuroprotective Activity ◽  
Mouse Retina ◽  
Mrna Levels ◽  
Neuroprotective Effects

The hematopoietic hormone erythropoietin (Epo), regularly produced by the kidneys and the liver, is also expressed in neuronal tissue, where it has been found to mediate paracrine neuroprotective effects. In most studies exploring the rescue effects of Epo, apoptosis was exogenously induced by different cell death stimuli. Herein, we set out to study the expression and function of Epo in physiologically occurring apoptosis in a model of retinal development. We made use of an organotypic retinal wholemount culture system that resembles the physiological in vivo situation with cell connections still retained. Epo mRNA expression in the retina, liver, and kidney showed a significant increase during early development, coinciding with the anemia of the newborn. In the retina of Epo-green fluorescent protein transgenic mice, Epo-expressing cells were identified and found to be distributed in the retinal ganglion cell layer. Treatment of retinal wholemount cultures with recombinant Epo resulted in a significant decrease of apoptotic ganglion cells as well as photoreceptor cells throughout retinal development. Moreover, transforming growth factor-β-induced apoptosis was completely antagonized by Epo when both factors were simultaneously applied. Investigations on the signaling pathway revealed a decrease in Bax mRNA levels in Epo-treated retinal cells. We conclude that Epo exerts wide and prolonged neuroprotective activity in physiologically occurring apoptosis and thus contributes to proper retinal development.

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