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Friend or Foe? The Role of Transforming Growth Factor-β (TGFβ) Signaling in Calcineurin Inhibitor-Induced Renal Damage

Ume, Adaku
http://orcid.org/0000-0003-0219-8172
http://rave.ohiolink.edu/etdc/view?acc_num=wright1679088380913241

Abstract Details

2023, Doctor of Philosophy (PhD), Wright State University, Biomedical Sciences PhD.
With its incorporation into clinical practice in the early 1980s, the class of pharmacological agents known as calcineurin inhibitors (CNIs) quickly became the cornerstone of immunosuppressive therapy post-organ transplantation. However, its use is limited by irreversible kidney damage in the form of renal fibrosis. The molecular mechanism by which CNIs induce renal fibrosis remains to be better understood, and to date, there are no specific therapeutic strategies to mitigate this damage. This dilemma presents a critical need to explain mechanisms by which CNIs cause renal damage. Kidneys of patients on chronic CNI therapy show increased expression of the proinflammatory cytokine Transforming Growth Factor β (TGFβ). TGFβ is a multipotent regulator of cell survival, differentiation, proliferation, and extracellular matrix (ECM) production in a variety of tissues. Renal biopsy samples from patients with tacrolimus nephrotoxicity showed both increased mRNA and protein expression of TGFβ along with fibronectin and collagen, additional profibrotic markers. However, the role of TGFβ signaling in CNI-induced renal damage remains to be defined and this gap in knowledge prompts further investigation. To this end, this dissertation will I) determine the role of TGFβ signaling in CNI-induced renal damage (Aim 1) and II) establish whether disruption of TGFβ signaling ameliorates renal damage with CNI-induced immunosuppression (Aim 2). This insight will direct development of newer generation CNI immunosuppressants exhibiting reno-preservative potential. Our group reported that aberrant Transforming Growth Factor-β (TGFβ)/Smad signaling drives the profibrotic effects induced by CNIs. Specifically, we demonstrated that 1) tacrolimus inhibits the calcineurin/NFAT axis while inducing TGFβ ligand secretion and receptor activation in renal fibroblasts, 2) aberrant TGFβ receptor activation stimulates Smad-mediated production of myofibroblast markers, notable features of fibroblast-to-myofibroblast transition (FMT) and 3) FMT contributes to extracellular matrix (ECM) expansion in tacrolimus-induced renal fibrosis. These findings spurred follow-up studies investigating the feasibility in inhibiting TGFβ receptor activation to maintain CNI-mediated immunosuppression while ultimately preserving kidney health. We found that inhibition of TGFβ signaling 1) promotes positive effects such as the attenuation of tacrolimus-induced interstitial fibrosis and fibroblast activation. However, disruption of TGFβ signaling also exacerbates CNI-related nephrotoxic effects such as disruption of both 2) glomerular and 3) tubular functions. Taken together, these results indicate that renal TGFβ signaling exerts both beneficial and detrimental effects, which establish its role as both a friend and foe in the kidney. Given this revelation, directly targeting TGFβ signaling is not a suitable approach to prevent the renal damage associated with CNI therapy.
Clintoria Williams, Ph.D. (Advisor)
Mark Rich, M.D., Ph.D. (Committee Member)
Eric Bennett, Ph.D. (Committee Member)
David Cool, Ph.D. (Committee Member)
Khalid Elased, Pharm.D., Ph.D. (Committee Member)
129 p.
Biology; Biomedical Research; Medicine; Pathology; Pharmacology; Physiology
calcineurin inhibitors; tacrolimus; Transforming Growth Factor-β; renal damage; renal fibrosis; fibroblasts; myofibroblasts; nephropathy

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Citations

  • Ume, A. (2023). Friend or Foe? The Role of Transforming Growth Factor-β (TGFβ) Signaling in Calcineurin Inhibitor-Induced Renal Damage [Doctoral dissertation, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1679088380913241

    APA Style (7th edition)

  • Ume, Adaku. Friend or Foe? The Role of Transforming Growth Factor-β (TGFβ) Signaling in Calcineurin Inhibitor-Induced Renal Damage. 2023. Wright State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1679088380913241.

    MLA Style (8th edition)

  • Ume, Adaku. "Friend or Foe? The Role of Transforming Growth Factor-β (TGFβ) Signaling in Calcineurin Inhibitor-Induced Renal Damage." Doctoral dissertation, Wright State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=wright1679088380913241

    Chicago Manual of Style (17th edition)

wright1679088380913241
174
© 2023, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.