Publication Date
2025
Document Type
Thesis
Committee Members
Khalid M. Elased, Pharm.D., Ph.D. (Advisor); Mauricio Di Fulvio, Ph.D. (Committee Member); Courtney Sulentic, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Diabetes mellitus is a leading cause of chronic kidney disease (CKD), primarily through dysregulation of the renin-angiotensin system (RAS), characterized by elevated Ang II which promotes vasoconstriction, oxidative stress, and renal fibrosis, along with increased urinary shedding of angiotensin converting enzyme 2 (ACE2), which can exacerbate the imbalance of RAS and tubular injury. Previous studies demonstrated that rosiglitazone, a PPAR-γ agonist, attenuated hyperglycemia, glycosuria, albuminuria, and decreased urinary ACE2 shedding in db/db mice, suggesting a RAS-mediated renoprotective mechanism. Building on this evidence, the current study compared the renal effects of pioglitazone (a PPAR-γ agonist) and canagliflozin (an SGLT2 inhibitor) in db/db diabetic mice over a period of 10-15-weeks. Both pioglitazone and canagliflozin significantly decreased hyperglycemia in db/db mice without affecting blood glucose in nondiabetic mice but exhibited divergent effects on renal outcomes. Pioglitazone suppressed renal a disintegrin and metalloproteinase 17 (ADAM17) expression, leading to reduced urinary ACE2 shedding and albuminuria, and upregulated renal ACE2, NEP, and SIRT1, highlighting its glomerular protective actions beyond glycemic control. In contrast, canagliflozin paradoxically increased urinary ACE2 shedding and albuminuria in db/db mice, while simultaneously upregulating renal SIRT1 and decreasing urinary NGAL levels, suggesting a renoprotective mechanism via tubular SIRT1-NGAL pathways. Importantly, canagliflozin-induced glycosuria in lean non-diabetic mice significantly increased albuminuria without altering urinary ACE2, indicating potential off-target renal effects in the absence of hyperglycemia. This differential response underscores the complexity of canagliflozin’s impact on renal physiology depending on the metabolic context. Together, these findings reveal distinct yet complementary mechanisms of renoprotection: pioglitazone through glomerular ADAM17-ACE2 modulation, and canagliflozin through tubular SIRT1 activation and NGAL reduction. The results highlight the potential for a combination therapeutic strategy targeting multiple pathways to more effectively mitigate the progression of diabetic nephropathy. This work advances the understanding of hyperglycemia, RAS imbalance, metalloproteinase activity, and tubular injury intersect in diabetic kidney disease, and supports future biomarker-driven and multi-targeted treatment approaches to prevent end-stage renal disease.
Page Count
129
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2025
Copyright
Copyright 2025, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0002-9948-8271
