The effects of high intensity interval training on markers of cellular and molecular health in an animal model of early-stage chronic kidney disease

Approximately 10% of Australians show signs of chronic kidney disease (CKD), an irreversible condition characterized by declining kidney function and reduced life expectancy. The majority of CKD-related complications stem from cellular and molecular damage associated with poor blood pressure regulation, exaggerated levels of oxidative stress and inflammation, and reductions in genomic stability. To help improve health, chronic aerobic exercise training is often recommended for CKD patients. In this regard, emerging evidence suggests high intensity interval training (HIIT) may be more beneficial than traditional chronic aerobic exercise. However, direct comparisons between HIIT and traditional chronic aerobic exercise as they pertain to factors associated with the development and progression of CKD are lacking. Through a series of six manuscripts, this thesis was designed with five aims in mind: (1) quantify the financial impact produced by CKD in Australia; (2) review the scientific evidence relating to factors associated with the development and progression of CKD; using an animal model of early-stage CKD, compare the effects of low intensity aerobic exercise and HIIT, as they relate to three of the primary factors associated with the development and progression of CKD, by examining: (3) tissue-specific mRNA expression of genes related to blood pressure regulation; (4) renal-specific mRNA expression of genes related to antioxidant enzyme activity and inflammation, as well as plasma levels of oxidative stress; (5) renalspecific mRNA expression of genes related to genomic stability. Manuscript 1 demonstrates the financial impact of CKD on the Australian healthcare system. Between 2012 and 2020, prevalence, per-patient expenditure, and total disease expenditure are estimated to increase by 29%, 16%, and 37% respectively. These CKD-related rates of increase are significantly higher than the same measures in cardiovascular disease, currently the most expensive disease group in Australia. Manuscripts 2 and 3 review factors associated with the development and progression of CKD. Manuscript 2 identifies the most pertinent markers of oxidative stress in patients with CKD and highlights promising novel markers. Manuscript 3 discusses the cyclical and exacerbatory relationship between factors associated with the development and progression of CKD, as well as the role of CKD in the development and progression of other diseases. Both reviews discuss emerging evidence that advocates chronic aerobic exercise as potentially therapeutic in CKD. Furthermore, chronic aerobic exercise is effective, inexpensive, and widely accessible, making it especially attractive in light of the findings presented in Manuscript 1. Based on evidence outlined in Manuscripts 2 and 3, Manuscripts 4-6 examine the effects of eight weeks of HIIT (85% VO2max), low intensity exercise (LIT; 45-50% VO2max), and sedentary behaviour (SED) as they relate to the development and progression of CKD. Manuscript 4 examined the tissue-specific expression of genes related to blood pressure regulation and CKD-related clinical markers. HIIT resulted in reduced Agt mRNA expression (v. LIT), improved plasma levels of LDL, triglycerides, and total cholesterol (v. LIT), improved plasma levels of albumin (v. SED and LIT), and reduced remnant kidney weight and kidney weight-body weight ratios (v. SED and LIT). Manuscript 5 examined the renalspecific mRNA expression of genes related to antioxidant enzyme activity and inflammation, and a plasma marker of oxidative stress. HIIT resulted in increased mRNA expression of Sod1 (v. SED), Cat (v.SED and LIT), and Tnfrsf1b (v. LIT). Manuscript 6 examined the renal-specific mRNA expression of genes related to genomic stability. HIIT resulted in increased Fan1 mRNA expression (v. SED) and telomere length as measured by T/S ratio (v.SED and LIT). This thesis represents a significant and original contribution to the scientific literature by means of a unique approach that highlights the financial impact of CKD in Australia and by elucidating mechanisms by which HIIT may be a superior form of chronic aerobic exercise (v. SED and LIT) in patients with CKD. The application of these findings may influence healthcare professionals’ prescription of exercise, leading to improved outcomes in CKD patients.