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Investigating Runx2, BMP2 and Klotho expression in two hypertensive models of chronic kidney disease as drivers of vascular calcification

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posted on 2023-08-10, 02:57 authored by Ashleigh Hicks

Vascular calcification (VC) is a risk factor for cardiovascular mortality in chronic kidney disease (CKD). Upregulation of calcification promotors; runt-related transcription factor two (Runx2) and bone morphogenic protein two (BMP2), and downregulation of calcification inhibitors such as klotho, have emerged as contributors to VC development. However, most studies have taken place in severe renal impairment animal models, not representative of the progressive nature of human CKD. Therefore, this thesis aimed to investigate expression of Runx2 and BMP2 in the aorta and klotho within the kidneys of two hypertensive models of CKD, which develop over a less-acute timeframe than previously studied.  The two models include; 0.3% adenine-administration to spontaneously hypertensive rats (SHR) (7F/7M treated and 7F/7M controls) from 15-27 weeks of age, and the Lewis polycystic kidney (LPK) rat (7F and 7M) a genetic model of CKD, age 18 weeks. Lewis rats (7F and 7M) were used as controls for the LPK rats. Renal function was assessed by urine and plasma analysis, and creatinine clearance calculation. Tail-cuff was used for blood pressure measurement, and an o-cresolphthalein assay was used for VC measurement. Runx2 and BMP2 aorta expression (male SHRs and male LPKs) and klotho kidney expression (male SHRs) were assessed via qPCR.  Renal impairment of adenine-treated SHRs and LPK rats was comparable at endpoint, indicated by polydipsia, polyuria, reduced urine creatinine, and increased plasma urea. Adenine administration increased blood pressure in female SHRs but not males. However, the adenine-treated SHRs blood pressure was comparable to the LPKs. VC was only evident in the LPK cohort. Runx2 and BMP2 expression was not significantly different between the male hypertensive groups. Klotho expression was significantly reduced in male SHR adenine-treated kidneys.  This thesis presents two hypertensive models of CKD with comparable endpoint renal impairment. However, model refinement of our adenine-induced SHR model is required to ensure VC development. Expression of Runx2 and BMP2 in the aorta of male SHRs and male LPKs must be compared to normotensive animals before conclusions can be made. Klotho reduction in the adenine-treated SHR kidneys suggests Klotho deficiency as a pre-calcification event.

History

Table of Contents

1. Introduction -- 2. Methods -- 3. Results -- 4. Discussion -- 5. References

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Department, Centre or School

Macquarie Medical School

Year of Award

2023

Principal Supervisor

Jacqueline K. Phillips

Additional Supervisor 1

Cara M. Hildreth

Rights

Copyright: The Author Copyright disclaimer: https://www.mq.edu.au/copyright-disclaimer

Language

English

Extent

77 pages

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