Grant: Discovery Grants Program - Individual

When the kidneys are deprived of oxygen, hypoxia (low blood oxygen) can occur and chronic kidney diseases may follow. Despite intense research, the mechanisms that underlie the pathways to renal hypoxia remain poorly understood. That difficulty may be due to the complex interplay among the millions of renal tubules (nephrons) and vessels that forms the basis for the integrative function of the kidney but that remains to be fully characterized. Building on my team's expertise in developing computational models of the rat kidney that represent the complex interactions, we will extend those models and conduct the following research activities: (1) To develop a detailed computational model of integrative rat kidney function, and to use that model to examine key determinants of kidney function and medullary oxygenation. Simulations of gene knockout and nephron loss will be conducted to determine: What are the necessary nephron structures and functions that must be preserved or inhibited to increase oxygen balance in the vulnerable parts of the kidney, while maintaining overall kidney functions? (2) To simulate and gain insights into the development and impacts of renal hypoxia. Model simulations will be conducted to investigate factors that impact kidney tissue oxygen tension, particularly in the vulnerable outer medulla, including shift in Na+ transport to the more distal and less efficient nephron segments, elevated oxidative stress, hyperfiltration, and tubular hypertrophy. We will simulate and investigate the effectiveness of differing maneuvers and answer questions: How can one increase sodium excretion (motivated by hypertension treatment) while limiting effects on other kidney functions and preserve oxygenation? To what extent do blood pressure reduction maneuvers increase kidney oxygen tension and protect the organ? (3) To develop and apply computational models to analyze sex differences in kidney function. Recent experimental studies have revealed surprising and important sex-based differences along the nephron of the rodent kidney. To analyze that data, we will develop sex-specific computational models and conduct simulations to better understand sex differences in kidney function. In particular, we will study the differences in which male and female rats handle sodium and water, the key determinants of blood pressure set point. Our research program is novel in its use of computational modeling and simulations to study kidney function. The proposed computational models are unique in that they incorporate renal transport and metabolic processes at different biological scales, and that they represent sex differences in kidney function. The long-term goals of our research program are to seek insights into the key determinants of kidney function, and into how mutations in renal transporters affect kidney function and electrolyte homeostasis. Trainees supported by this award would have learned renal physiology, computational modeling, and numerical methods.