Date of Award
January 2017
Document Type
Thesis
Degree Name
Medical Doctor (MD)
Department
Medicine
First Advisor
Lloyd G. Cantley
Abstract
Previous studies have demonstrated that the loss of polycystins results in exaggerated cilia dependent cyst activating signaling, which results in pathologic tubule remodeling. Because the cilia polycystin complex can function as a flow sensor, we sought to evaluate whether an increase in glomerular filtration rate can modulate tubule diameter and, in pathologic cases, reproduce the cystic phenotype. We employed a compensatory nephrectomy model to induce hyperfiltration in the context of 1) a normal physiologic response and 2) the reduced expression of polycystin 1, which we hypothesized can sensitize the kidney to abnormal remodeling. To accomplish this, we use multiphoton microscopy and optimized image analysis techniques to accurately detect morphological changes in response to hyperfiltration. Our data demonstrated a reproducible 20% increase in tubular cross sectional area in response to nephrectomy in both WT and PKD heterozygote models. These studies not only support a model of tubular flow adaptation, but also demonstrate that the reduction of polycystin-1 in the context of hyperfiltration is insufficient to cause abnormal remodeling of tubular cross sectional area. Just as importantly, we also observed increased nuclear densities and lumen cross sectional areas that was concomitant with decreased tubular cell volumes in the PKD heterozygotes. We later extend our analysis into the inducible homozygous knockout of polycystin-1 where we modeled the morphologic changes that occur in the initial phase of cytogenesis.
Recommended Citation
Kurtz, Elizabeth Chen, "Three Dimensional Reconstructions Of Nephrons In Kidneys Disease" (2017). Yale Medicine Thesis Digital Library. 2138.
https://elischolar.library.yale.edu/ymtdl/2138
Comments
This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.