Patients with chronic kidney disease (CKD) are at an alarming risk of cardiovascular disease and fracture- associated mortality. CKD results in a sequelae of physiological changes, including a triad of abnormal biochemistries, bone remodeling changes and vascular calcification, that culminate in increased morbidity and mortality. There is a critical need to better understand the underlying mechanism driving altered cardiovascular and skeletal homeostasis, as well as any connection between the two. Chronic kidney disease has been shown to have negative effects on vascular reactivity and end-organ perfusion. Extensive work in CKD has documented vascular changes to the aorta, coronary vessels and gastrointestinal resistance arteries. Surprisingly, exploration of skeletal perfusion and vasculature has not been undertaken in CKD even though hyperparathyroidism is common in CKD and the role of PTH in modulating vasculature, including that of the bone, has been well- established in the literature. Alterations in bone blood flow are linked to dysregulation of bone remodeling and mass in multiple conditions. Based on the above scientific premise, the goal of the present study is to test the hypothesis that elevated PTH contributes to maladaptive changes to the skeletal vasculature that contribute to the skeletal deterioration in CKD. This study will explore connections between the cardiovascular and skeletal systems by studying the contributions of bone remodeling rate and parathyroid hormone levels on skeletal blood flow and vascular properties in the setting of CKD. This will be tested through the use of a slowly progressive model of CKD-MBD, the Cy/+ rat.
The first Aim i s to establish the effect of CKD on skeletal blood flow and vascular properties. This will be accomplished by examining bone blood flow and vascular reactivity of the principal nutrient artery (PNA) of the femur in 30 and 35-week-old Cy/+ rats and their normal littermates. These time points represent mild and severe CKD. Specifically, outcomes will include regional bone perfusion (tissue fluorescence density of injected fluorescent microspheres), PNA vascular reactivity (myogenic tone, endothelial- independent relaxation, endothelial-dependent relaxation and response to PTH), bone turnover (histomorphometry), and biochemistries.
The second Aim i s to uncouple the effects of remodeling suppression and PTH suppression on bone vasculature properties. This will be accomplished by treating Cy/+ rats with either parathyroidectomy (PTX; to lower PTH and bone remodeling) or bisphosphonate (to lower bone remodeling without affecting PTH). We expect that PTX will normalize both bone blood flow and PNA vascular reactivity, while bisphosphonate will not normalize bone blood flow or PNA vascular reactivity. An understanding of the detrimental impact of CKD on bone blood flow is a crucial step in understanding bone disease in these patients. This study provides an important step in achieving this goal by examining these changes and their potential corrections in a rat model with the spontaneous and progressive development of chronic kidney disease.

Public Health Relevance

Chronic kidney disease is becoming more prevalent worldwide. These patients are at an alarming risk of cardiovascular disease and fracture-associated mortality. This study will explore connections between the cardiovascular and skeletal systems by studying the contributions of bone remodeling rate and parathyroid hormone levels on skeletal blood flow and vascular properties in the setting of CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DK115162-01A1
Application #
9468919
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2017-09-30
Project End
2021-05-31
Budget Start
2017-09-30
Budget End
2018-09-29
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202