Unanswered Questions Regarding Sex and BMP/TGF-β Signaling

Shah, Tapan A.; Rogers, Melissa B.

doi:10.3390/jdb6020014

Cited by 25 publications

(14 citation statements)

References 73 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 5B).…”

Section: Sex Hormones Directly Influence the Expression Of Tgf-β1 And Bmp7 In Cortical Tissue From Mouse Kidneymentioning

confidence: 69%

“…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: Sex Hormones Directly Influence the Expression Of Tgf-β1 And Bmp7 In Cortical Tissue From Mouse Kidneymentioning

confidence: 69%

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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“…Males and persons of older age are known to have higher Tregs frequencies compared to females [119] , [120] , [121] and younger individuals [122] , [123] , [124] . Additionally, sex and age-related differences exist in the expression of immune checkpoints PD1 and CTLA4 [ 125 , 126 ], and, TGF-β1 [127] , [128] , [129] , [130] . In our study, we mainly included male individuals since the majority of participants in the Montreal primary infection (acute) cohort are male.…”

Section: Discussionmentioning

confidence: 99%

Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection

et al. 2021

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Background: HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied. Methods: Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIVinfected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology. Findings: Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-b1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-b7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-b1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-b1) + Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-b1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different. Interpretation: Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression. Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the R eseau SIDA et maladies infectieuses du Fonds de recherche du Qu ebec-Sant e (FRQ-S).

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“…Epithelial mesenchymal transition influences vascular calcification (Bostrom et al, 2016;Sanchez-Duffhues et al, 2019). Both quantitative and qualitative differences in aortic miRNA profiles in each sex may be highly clinically relevant because there are significant disparities in incidence, prognosis, and response to treatments for arterial diseases between men and women (den Ruijter et al, 2015) We are separately investigating the sex-associated differences in the context of a study aimed at clarifying the impact of sex on BMP signaling (Shah & Rogers, 2018).…”

Section: Discussionmentioning

confidence: 99%

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 25 publications

References 73 publications

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

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

Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection

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

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