Browsing by Subject "kidney"

Now showing 1 - 3 of 3
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    Genetic Variants Associated with Tacrolimus Metabolism in Kidney Transplant Recipients
    (2023-08) Dorr, Casey
    This master’s thesis focuses on the work completed during my K01 award Genetic Variants Associated with Tacrolimus (TAC) metabolism in Kidney Transplant Recipients. In Chapter 1, I discuss the significance and innovations of this project. In Chapter 2, I present reformatted manuscript published in the Pharmacogenomics Journal titled: Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing. In Chapter 3, I present a reformatted manuscript published in Drug Metabolism and Disposition titled: CRISPR/Cas9 genetic modification of CYP3A5 *3 in human hepatocytes leads to cell lines with increased midazolam and tacrolimus metabolism. Chapter 4 is the general conclusions, future directions and take away messages.
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    Interaction Of Afferent Renal Nerve Activity And Il-1R Signaling In Hypertension
    (2024-04) Baumann, Daniel
    Renal denervation was recently approved by the FDA for the treatment of hypertension, but the mechanism by which it reduces blood pressure is unclear. Studies of patients who have received the treatment have shown a variety of off-target improvements in conditions associated with sympathetic overactivity. One explanation is that these effects are due to ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. Renal interleukin 1-beta (IL-1β) is elevated in many cases of hypertension, as well as the DOCA-salt model of hypertension, and its activity may be responsible for the elevation in afferent renal nerve activity and arterial pressure. IL-1R activation increases the activity of afferent sensory nerves in other contexts. In these studies, I sought to determine if IL-1R activity was responsible for the increased afferent renal nerve activity characteristic of DOCA-salt hypertension. First, I characterized a mouse model of DOCA-salt hypertension and found that ablation of the afferent renal nerves attenuates hypertension in this model. Next, I used this model in combination with two methods of IL-1R disruption: genetic IL-1R knockout and pharmacological IL-1R antagonism. These methods attenuated hypertension in this model system. Further, combining either method with afferent renal denervation produced no additional attenuation of hypertension, and an acute depressor response to delivery of the IL-1R antagonist was observed only in animals with intact renal afferent nerves, indicating a common mechanism of action. In combination, these findings suggest that IL-1R activation is partially responsible for the elevated afferent renal nerve activity which stimulates central sympathetic outflow to renal and non-renal targets to drive DOCA-salt hypertension.
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    The role of hepatocyte nuclear factor 1 beta in kidney development and disease
    (2022-09) Shao, Annie
    The transcription factor hepatocyte nuclear factor 1β (HNF-1β) is essential for normal development of the kidney and other epithelial organs. Mutations of HNF1B in humans produce cystic kidney diseases, including congenital anomalies of the kidney and urinary tract (CAKUT) and autosomal dominant tubulointerstitial kidney disease (ADTKD). CAKUT is one of the most common birth defects and most common causes of pediatric end-stage renal disease. There are no curative treatments for CAKUT. Individuals with CAKUT may need lifelong dialysis or kidney transplant. CAKUT is caused by a perturbation of kidney development. Mammalian kidney development involves reciprocal cell signaling between two primordia: the metanephric mesenchyme (MM), which gives rise to nephrons, and the ureteric bud (UB), which gives rise to the collecting duct system. HNF-1β is required for the differentiation and patterning of immature nephrons and branching morphogenesis of the UB. Kidney-specific ablation of HNF-1β in mice during development causes branching morphogenesis failure and hypoplastic kidneys. In addition, kidney-specific ablation of HNF-1β after kidney development in mice leads to cystic kidney disease. In the studies presented here, we examined the role of HNF-1β in fibrosis in HNF1B-related ADTKD using transgenic mouse models and lineage tracing. We optimized ex vivo metanephric organ culture and 3D imaging as a method of quantifying UB branching morphogenesis and tested several gene manipulation strategies for ex vivo kidney culture. We used ChIP-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to identify genes that are regulated by HNF-1β in embryonic mouse kidneys. These studies found that HNF-1β directly regulates the expression of multiple axon guidance genes in the developing mouse kidney. Dysregulation of axon guidance genes may underlie kidney defects in HNF-1β mutant mice. We used ChIP-seq and RNA-seq to identify genes that are regulated by HNF-1β in adult mouse kidneys. We compared genes and pathways regulated by HNF-1β in adult and embryonic mouse kidneys. We found that HNF-1β also regulates axon guidance in adult kidneys. Collectively, these studies identify novel pathways HNF-1β regulates in the developing kidney and adult kidney whose dysregulation leads to kidney disease.