Unanswered Questions Regarding Sex and BMP/TGF-&amp;beta; Signaling

Shah, Tapan A.; Rogers, Melissa B.

doi:10.20944/preprints201805.0180.v1

Cited by 6 publications

(3 citation statements)

References 51 publications

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“…Our data also suggest that DHT affects TGF-β1 expression differently depending on the diabetes phenotype in male kidney tissue: DHT decreases TGF-β1 mRNA levels in non-diabetic tissues and increases them in diabetic tissues compared to DMSO control in the same males. Other studies also show that both in vitro and in vivo TGF expression can be differentially influenced by DHT, which in these studies was dependent on the cell type or DHT concentration [ 34 , 55 , 73 ]. In kidney tissue from female mice, DHT has minimal or inhibitory effects on TGF-β1 mRNA expression compared to DMSO control, regardless of whether the donor females were diabetic or non-diabetic ( Figure 5 B).…”

Section: Resultsmentioning

confidence: 99%

“…Yet, precise mechanisms by which sex hormones contribute to the pathophysiology of diabetic renal disease are poorly characterized. Sex hormones regulate many members of the BMP/TGF-β signaling pathways, which in turn strongly influence fibrotic processes in DN; other than this, very few studies have addressed the regulation of these pathways in a sex-dependent manner (reviewed in [ 34 ]).…”

Section: Introductionmentioning

confidence: 99%

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Sex Differences in Diabetes- and TGF-β1-Induced Renal Damage

Ziller

Kotolloshi

Esmaeili

et al. 2020

Cells

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While females are less affected by non-diabetic kidney diseases compared to males, available data on sex differences in diabetic nephropathy (DN) are controversial. Although there is evidence for an imbalance of sex hormones in diabetes and hormone-dependent mechanisms in transforming growth factor β1 (TGF-β1) signaling, causes and consequences are still incompletely understood. Here we investigated the influence of sex hormones and sex-specific gene signatures in diabetes- and TGF-β1-induced renal damage using various complementary approaches (a db/db diabetes mouse model, ex vivo experiments on murine renal tissue, and experiments with a proximal tubular cell line TKPTS). Our results show that: (i) diabetes affects sex hormone concentrations and renal expression of their receptors in a sex-specific manner; (ii) sex, sex hormones and diabetic conditions influence differences in expression of TGF-β1, its receptor and bone morphogenetic protein 7 (BMP7); (iii) the sex and sex hormones, in combination with variable TGF-β1 doses, determine the net outcome in TGF-β1-induced expression of connective tissue growth factor (CTGF), a profibrotic cytokine. Altogether, these results suggest complex crosstalk between sex hormones, sex-dependent expression pattern and profibrotic signals for the precise course of DN development. Our data may help to better understand previous contradictory findings regarding sex differences in DN.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex Differences in Diabetes- and TGF-β1-Induced Renal Damage

Ziller

Kotolloshi

Esmaeili

et al. 2020

Cells

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“…It is likely that a major mechanism whereby estrogen exerts its protective effects is via the suppression of TGF-β-dependent extracellular matrix production and accumulation and downregulation of non-collagenous proteins (71) in cardiovascular lesions, both of which likely serve to prevent increases in micro-environmental stiffness that increase the propensity for apoptosis in response to sustained elevations in TGF-β (72). The interactions between sex hormones and TGF-β signaling are remarkably complex and context dependent, however, and entire reviews have focused on this topic and unanswered questions in the field (73). Furthermore, given previous work suggesting that TGF-β can reciprocally inhibit estrogen receptor signaling via a canonical smad4 interaction (74, 75), the extent to which systemic estrogens can be increased to win over this interplay remains unclear.…”

Section: Role Of Estrogens In the Regulation Of Cardiovascular Calcifmentioning

confidence: 99%

Influences of Sex and Estrogen in Arterial and Valvular Calcification

Zhang

Miller

2019

Front. Endocrinol.

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Vascular and cardiac valvular calcification was once considered to be a degenerative and end stage product in aging cardiovascular tissues. Over the past two decades, however, a critical mass of data has shown that cardiovascular calcification can be an active and highly regulated process. While the incidence of calcification in the coronary arteries and cardiac valves is higher in men than in age-matched women, a high index of calcification associates with increased morbidity, and mortality in both sexes. Despite the ubiquitous portending of poor outcomes in both sexes, our understanding of mechanisms of calcification under the dramatically different biological contexts of sex and hormonal milieu remains rudimentary. Understanding how the critical context of these variables inform our understanding of mechanisms of calcification—as well as innovative strategies to target it therapeutically–is essential to advancing the fields of both cardiovascular disease and fundamental mechanisms of aging. This review will explore potential sex and sex-steroid differences in the basic biological pathways associated with vascular and cardiac valvular tissue calcification, and potential strategies of pharmacological therapy to reduce or slow these processes.

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MicroRNA Profiles in Calcified and Healthy Aorta Differ: Therapeutic Impact of miR-145 and miR-378

Tang

Shah

Yurkow

et al. 2019

Preprint

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Our goal was to elucidate microRNAs (miRNAs) that may repress the excess bone morphogenetic protein (BMP) signaling observed during pathological calcification in the Klotho mouse model of kidney disease. We hypothesized that restoring healthy levels of miRNAs that post-transcriptionally repress osteogenic calcific factors may decrease aortic calcification. Our relative abundance profiles of miRNAs in healthy aorta differ greatly from those in calcified mouse aorta. Unbiased analyses of KEGG and GO term associated genes suggest that these miRNAs regulate proteins involved in many essential processes, including osteogenesis. Two differentially regulated miRNAs, miR-145 and miR-378, were selected based on three criteria: reduced levels in calcified aorta, the ability to target more than one protein in the BMP signaling pathway, and conservation of targeted sequences between humans and mice. Forced expression using a lentiviral vector demonstrated that restoring normal levels repressed the synthesis of BMP2 and other pro-osteogenic proteins and inhibited pathological aortic calcification in mice with renal insufficiency. This study identified miRNAs that may impact BMP signaling in both sexes and demonstrated the efficacy of selected miRNAs in reducing aortic calcification in vivo. Calcification of the aorta and the aortic valve resulting from abnormal osteogenesis is common in those with kidney disease, diabetes, and high cholesterol. Such vascular osteogenesis is a clinically significant feature. The calcification modulating miRNAs described here are candidates for biomarkers and "miRNA replacement therapies" in the context of chronic kidney disease and other pro-calcific conditions.

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Unanswered Questions Regarding Sex and BMP/TGF-β Signaling

Cited by 6 publications

References 51 publications

Sex Differences in Diabetes- and TGF-β1-Induced Renal Damage

Sex Differences in Diabetes- and TGF-β1-Induced Renal Damage

Influences of Sex and Estrogen in Arterial and Valvular Calcification

MicroRNA Profiles in Calcified and Healthy Aorta Differ: Therapeutic Impact of miR-145 and miR-378

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