Transforming Medicine Through Physiology

Claude Bernard is considered by many to be the father of modern physiology and medicine. In his 1865 book, An Introduction to the Study of Experimental Medicine, Bernard introduced the scientific method to the field of medicine and thereby initiated the concept of evidenced-based medicine. In this approach, physiological research focuses on finding solutions for clinical problems through hypothesis-driven research. In this regard, the interaction between clinician and scientist is critical. Bernard clearly understood this when he stated, “The experimenter who does not know what he is looking for will not understand what he finds.” Today, 150 years later, the discoveries made through physiological research have transformed medical practice, and in many respects physiology is medicine. In his invited editorial in this issue of Physiology, Dr. Jeff Sands emphasizes the role of renal physiology in the advances made in clinical nephrology. Sands refers to the recommendations of the Kidney Research National Dialogue initiated by the National Institute of Diabetes and Digestive and Kidney Diseases, which identified research objectives that would improve basic knowledge of kidney physiology and thereby impact the treatment of kidney disease. Along this line, several review articles in this issue of Physiology illustrate how targeted physiological research has and will continue to transform medicine. Research in renal physiology has provided considerable insight into the complexity and limits of kidney circulatory adaptations in response to reductions in blood flow. It has been demonstrated that occlusive renovascular disease caused by atherosclerotic renal artery stenosis elicits complex pathophysiological responses that eventually lead to loss of kidney function. In their review (6), Saad and colleagues emphasize that reductions in oxygen related to vascular disease ultimately trigger inflammatory injury that continues to drive scarring in the kidney even after restoration of main vessel blood patency. Several randomized prospective clinical trials have shown that stent revascularization alone in patients with atherosclerotic renal artery stenosis provides little additional benefit to medical therapy once these inflammatory processes have developed and solidified. Experimental data now support developing adjunctive cell-based measures to support angiogenesis and promote anti-inflammatory renal repair mechanisms. Modifying the inflammatory response using mesenchymal stem cell therapy in the kidney offers the potential to recover small vessels and limit kidney injury. These data support the use of cell-based therapy to protect injured kidneys and prevent progression to advanced kidney failure. Research in renal physiology has also shown that macrophages play a key role in both normal and diseased kidneys. Macrophages are involved in the clearance of cellular debris, tissue immunesurveillance, and cellular repair. These cells display considerable phenotypic diversity, and thus their roles in the development, progression, and resolution of a broad range of kidney diseases are equally diverse. For example, pathophysiological changes in some disease states induce pro-inflammatory macrophages that further exacerbate tissue injury, inflammation, and subsequent fibrosis. In contrast, physiological changes may also induce anti-inflammatory macrophages that mediate kidney repair and regeneration. In their review (2), Cao et al. summarize the diverse roles of different macrophage phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. Understanding what alterations of the kidney microenvironment occur and how these factors control macrophage phenotype and functions may unveil novel therapeutic targets to limit injury and restore function in kidney disease. Research in renal physiology has also provided mechanistic insight into autosomal-dominant polycystic kidney disease (ADPKD), which is the most common inherited kidney disease. More than half of affected patients develop kidney failure requiring dialysis or kidney transplantation due to the development of multiple kidney cysts. In addition, ADPKD affects other organs such as the heart, liver, and brain, which can lead to life-threatening conditions. In their review (7), Saigusa and Bell discuss how physiological research has provided a better understanding of cyst development, including the role of primary cilia and polycystins in ADPKD. An approved treatment for ADPKD is currently unavailable, but research has revealed several potential therapeutic targets that may slow disease progression. Indeed, several drugs are currently being tested in human clinical trials. Such treatments will significantly reduce the overall mortality rate in people with ADPKD. Physiological research has also impacted other areas of medicine. By the year 2030, 20% of the population in the United States will be over the age of 65. This demographic change will result in a greater incidence of chronic diseases that will require substantial investments in health care. Aging is accompanied by the onset of sarcopenia, the age-related loss of muscle mass, which negatively impacts both muscle strength and endurance, in addition to creating a higher risk for the development of chronic metabolic diseases. Mitochondria are essential organelles for skeletal muscle health and exhibit age-related changes that may underlie sarcopenia. In their review (3), Carter and colleagues discuss physiological research exploring the cellular and molecular mechanisms that connect age-related mitochondrial changes to sarcopenia. Age-related decrements in mitochondrial quality may reflect changes in the molecular pathways responsible for both mitochondrial synthesis (biogenesis) and degradation/repair (mitophagy). Physical inactivity in old age may impact these molecular pathways, leading to diminished mitochondrial quality. It is well know that aerobic exercise induces both mitochondrial biogenesis and mitophagy, thereby improving mitochondrial quality. Older individuals who participate in aerobic exercise stimulate mitochondrial adaptations that improve muscle function and quality of life. However, it is unclear how age-related mitochondrial biogenesis and mitophagy interact with sarcopenia. Improved mitochondrial quality PHYSIOLOGY IN PERSPECTIVE Gary Sieck, Editor-in-Chief Mayo Clinic, Rochester, Minnesota PHYSIOLOGY 30: 173–174, 2015; doi:10.1152/physiol.00013.2015