Mathematical Models of Kidney Function: Effects of Hypertension and Circadian Rhythm

Abstract

Hypertension induced by chronic angiotensin II (Ang II) infusion serves as a valuable experimental model for studying blood pressure regulation and the kidney's role in electrolyte and fluid homeostasis. The kidney's function is modulated by the renin-angiotensin-aldosterone system (RAAS) and circadian rhythms, with notable differences observed between males and females in the former. Under normotensive conditions, female rat nephrons exhibit lower Na+/H+ exchanger 3 (NHE3) activity in the proximal tubule but higher Na+ transporter activities along distal segments compared to males. Chronic Ang II infusion reduces NHE3 activity, shifts Na+ transport downstream, and promotes vasoconstriction, anti-natriuresis, and hypertension. These effects are further influenced by diurnal oscillations in glomerular filtration, electrolyte transport, and renal transporter regulation by circadian clock genes.

Using computational models of kidney function, this thesis explores two key areas: (i) the impact of Ang II infusion on segmental electrolyte transport and diuretic responses in male and female rat nephrons, and (ii) the influence of diurnal rhythms on the natriuretic and diuretic effects of loop, thiazide, and K+-sparing diuretics under normotensive and hypertensive conditions in male rats. Simulations suggest that NHE3 downregulation in the proximal tubule is a primary driver of natriuresis and diuresis, with stronger effects in males. In hypertension, the downstream shift in Na+ transport load amplifies the effects of diuretics, with hypertensive females exhibiting larger relative increases in Na+ excretion due to their higher distal transport load. Additionally, diuretic responses vary by time of day, with qualitatively similar diurnal oscillations observed in normotensive and hypertensive kidneys. These findings provide insights into sex-specific and time-dependent responses to hypertension and diuretic therapies, emphasizing the need to consider both physiological context and administration timing in treatment strategies.