Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/28958
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Krepinsky, Joan | - |
dc.contributor.author | Soomro, Asfia | - |
dc.date.accessioned | 2023-09-29T18:35:36Z | - |
dc.date.available | 2023-09-29T18:35:36Z | - |
dc.date.issued | 2023 | - |
dc.identifier.uri | http://hdl.handle.net/11375/28958 | - |
dc.description.abstract | Chronic kidney disease (CKD) affects around 11% of people in North America and is expected to rise. CKD is characterized by the development of fibrosis requiring kidney transplant or dialysis to survive as a direct result of impaired kidney function. TGFβ1 is a prominent profibrotic mediator in this context and is secreted by mesangial cells, tubular cells and fibroblasts. These cells once activated contribute to excessive production of extracellular matrix (ECM) proteins deteriorating functional renal tissue. The direct inhibition of TGFβ1 has limitations due to adverse effects in humans that alternative methods have gain popularity. Here, we discover activin A (actA), a member of TGFβ1 superfamily, playing a crucial role in sustaining the chronic effects of TGFβ1. Activins are multifunctional secreted cytokines synthesized as homo- or hetero-dimers of inhibin β subunits A, B, C or E. Previously, there have been attempts at blocking actA using various inhibitors such as a naturally occurring antagonist called follistatin (FST), ActRIIA/B trap and antibody. However, there is the risk of uncertain side effects due to their non specificity in blocking other ligands important to various cellular processes. Similarly, other variants of activins such as actAC has been shown to abrogate actA-induced pSmad2/3 signaling however little is known about their long-term effects. It is important to note that actA has been found highly elevated in serum and kidneys from human and mice with CKD. We hypothesize that actA regulates both canonical and noncanonical pathways to control TGFβ1-induced profibrotic responses. In the first study, within mesangial cells (MCs), the profibrotic effects of TGFβ1 are sustained primarily through the secretion of actA as it promotes Smad3 phosphorylation and transcriptional activity when MCs exhibit reduced sensitivity to TGFβ1 but not actA. This in part is facilitated by actA upregulating TGFβ1 receptor type II helping continue downstream signaling. Furthermore, actA enhances transcription through activation of MRTF-A, Smad3 co-activator fibrotic genes. Notably, actA neutralization effectively inhibits fibrosis induced by unilateral ureteral obstruction (UUO) in wildtype mice. Interestingly, TGFβ1-overexpressing mice with CKD (UUO) exhibit worsened fibrosis, accompanied by increased renal expression of actA and that its neutralization mitigated these outcomes. In the second study, we established a novel 5/6 nephrectomy animal model overexpressing TGFβ1 in C57BL/6 background mice resistant to hypertension and fibrosis to directly assess for actA faciliatory role in the maladaptive epithelial-mesenchymal crosstalk from long-term tubulointerstitial fibrosis caused by TGFβ1. TGFβ1 induces secretion of actA from tubular cells and actA neutralization prevents TGFβ1 profibrotic response in renal fibroblasts, interestingly, through Smad3 and YAP. This led us to our third study, which was to investigate TGFβ1’s regulation of the actA gene (INHBA). Results reveal critical transcription factors (Stat5, Foxp1 and Smad3) controlling actA promoter activity within 350 bp region of actA promoter. Targeting actA inhibition shows promise as an antifibrotic approach with potentially better clinical tolerability than direct TGFβ1 inhibition. | en_US |
dc.language.iso | en | en_US |
dc.title | UNDERSTANDING HOW ACTIVINS CONTRIBUTE TO TGFß1 PROFIBROTIC SIGNALIING IN CHRONIC KIDNEY DISEASE | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences (Blood and Cardiovascular) | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Candidate in Philosophy | en_US |
dc.description.layabstract | Chronic kidney disease (CKD) is becoming a rising health issue, seen in about 11% of people in North America. High blood pressure and diabetes are the most common causes of CKD. Over time, these cause scarring in the kidneys, leading to damage of the filtering units of the kidneys called glomeruli. As scarring builds up over time, kidney function becomes worse until kidneys fail. The goal of my thesis is to understand the scarring process better in an effort to develop new therapies to prevent scarring. We know that the protein TGFβ1 increases in CKD, and that it leads the cells in the kidneys to make scar proteins. Unfortunately, treatments which directly block TGFβ1 have too many side effects to be used in people since TGFβ1 also has other important functions not related to scarring. However, we found that TGFβ1 needs another protein called activin for it to cause cells to make scar proteins. Activin is increased in kidney disease, but not found in normal kidney tissue. This thesis explains whether blocking activin prevents scarring and thus kidney disease in CKD mice which have high levels of TGFβ1. Last, this thesis showed that TGFβ1 caused cells to make more activin and goes over how this happens to better understand how activin levels are controlled supporting the testing of activin blockers in people with CKD. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Soomro_Asfia_FinalSubmission2023Sept_PhD.pdf | 9.01 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.