Advisory Committee Chair
Anupam Agarwal
Advisory Committee Members
Christian Faul
James F George
Paul W Sanders
Adam R Wende
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Kidneys are physiologically vital organs responsible for blood homeostasis preservation through fluid balance maintenance, blood pressure regulation, hormone production, and toxic compound removal. Acute kidney injury (AKI) is a global condition affecting more than 13 million people yearly, and is characterized by a rapid decline in renal filtration capacity, consequent rise in serum creatinine and nitrogenous waste levels, and is associated with an elevated risk of morbidity in the form of progressive chronic kidney disease, kidney failure, and mortality. AKI-induced renal epithelial cell death forces surviving tubular cells to undergo de-differentiation, rapid proliferation to replace lost cells, and re-differentiation to assume a pre-insult phenotype. Such vast change in function is accompanied by an extended metabolic reprogramming, with aerobic glycolysis induction (Warburg effect) being a key player. Failure of renal cells to re-differentiate has been associated with diminished kidney recovery outcomes, which highlights glycolytic switch as a potential therapeutic target. AKI is associated with rapid macrophage infiltration and their subsequent polarization towards a pro-inflammatory (M1) profile accompanied by drastic metabolic reprogramming which allows them to conduct appropriate innate immune functions. Lactate Dehydrogenase A (LDHA) plays a major role in the aerobic glycolytic switch that is a key process in both M1 macrophage polarization and renal tubular cell de-differentiation. The purpose of my thesis is to iv investigate the role of LDHA in renal disease and inflammation as a potential target for the mediation of AKI. The conducted studies resulted in an improved understanding of the LDHA and its counterpart, LDHB, localization in both healthy kidneys, and spatiotemporal change in their expression post-AKI. I have developed a murine model of proximal tubule-specific LDHA deletion to conduct in vivo studies to further elucidate the LDHA-mediated response in AKI. Lastly, I utilized bone marrow-derived macrophages (BMDMs) that lacked the LDHA expression and investigated their ability to differentiate, polarize, and induce inflammation concluding that LDHA is crucial for the induction of functioning pro-inflammatory phenotype. Taken together this research work expands on the understanding of the role that LDHA plays in underlying mechanisms and inflammatory responses in AKI.
Recommended Citation
Osis, Gunars, "Renal Lactate Dehydrogenase A: Underlying Mechanisms and Inflammatory Roles in Acute Kidney Injury" (2022). All ETDs from UAB. 168.
https://digitalcommons.library.uab.edu/etd-collection/168