Background
          The neurohumoral systems and kidneys are intimately linked in the control of cardiovascular dynamics. Our previous experimental and theoretical studies suggest that abnormalities of kidney function, manifest by impaired pressure natriuresis, underlie all forms of hypertension studied thus far. In some cases, these disturbances originate intrarenally, but often they occur via activation of neurohumoral mechanisms that impair renal excretory capability. Therefore, a large share of our research has been directed toward understanding the intrarenal and neurohumoral mechanisms that regulate kidney function, and how they are altered in pathophysiologic conditions such as hypertension.

          Is obesity a primary cause of human essential hypertension? During the past several years, we have studied extensively obesity hypertension, which may have special relevance to human essential hypertension. Currently, 30-35% of the adult population in the United States is overweight, with a body mass index (BMI) greater than about 27 kg/m2. In certain populations, such as elderly African-American women, the prevalence of obesity may be as high as 70-80%, similar to their prevalence of hypertension. Population studies have clearly documented the relationship between obesity and hypertension; hypertension usually occurs in populations that have an increase in body weight with aging, but is rare when body weight does not increase with aging. Also, 75-85% of essential hypertensive subjects are overweight, an observation that is consistent with the hypothesis that excess weight gain is responsible, in large part, for the high prevalence of essential hypertension in industrialized societies.

          Is obesity a major risk factor for vascular disease and end-stage kidney failure? Although it is widely recognized that even modest overweight is an independent predictor of vascular disease, stroke, congestive heart failure, and cardiovascular death, obesity may also be a major cause of glomerulosclerosis and end-stage renal disease (ESRD). According to the United States Renal Data Systems Survey, the two leading causes of ESRD are diabetes and hypertension. At least 80-90% of diabetics are type II (non-insulin dependent diabetics (NIDDM), who are almost invariably overweight. Moreover, the majority of hypertensive patients are overweight, and there is evidence that excess weight is a major cause of human essential hypertension. These considerations suggest that obesity may also be one of the most important causes of ESRD. However, the mechanisms that link obesity with renal injury, especially the early changes that precede severe glomerulosclerosis and nephron loss, are poorly understood.

Previous Work in Our Laboratory
          Increased dietary fat intake in animals mimics obesity hypertension in humans. A major problem in studying the mechanisms of obesity hypertension has been the lack of animal models that closely resemble the physiological changes found in obese humans and that can be used to analyze, comprehensively, time-dependent changes in cardiovascular and kidney function that occur with weight gain. Although there are many genetic rodent models of obesity, the cardiovascular and renal changes that occur in most of these models have not been well characterized. In genetic rat models that have been extensively studied, the cardiovascular, renal and endocrine changes observed often do not mimic those found in obese humans. However, obesity hypertension in animals fed a high fat diet closely mimics obesity hypertension in humans. Two models that we have studied extensively are obese dogs and rabbits fed a high fat diet. In these models, the metabolic, endocrine, renal and cardiovascular changes closely resemble those found in obese humans.

          Cardiovascular changes in obesity. In dogs placed on a high fat diet for 5 weeks, with a constant intake of Na+, protein and carbohydrates, we found parallel increases in body weight and blood pressure, with arterial pressure increasing by approximately 15-20 mmHg. A high fat diet also increased heart rate and cardiac output by more than 50%. The increased herat rate appears to be caused mainly by decreased parasympathetic stimulation of the heart. The rise in cardiac output with weight gain is due, in part, to the additional adipose tissue and the blood flow associated with it. However, blood flows in non-adipose tissues, including the heart, kidneys, gastrointestinal tract and skeletal muscle also increase with weight gain. Despite the increased cardiac output, there is evidence of impaired diastolic and systolic function of the heart in obesity, even after only a few weeks of a high fat diet. However, the mechanisms that impair cardiac function in obesity are unknown and an important area for further research.

          Obesity impairs renal excretory capability. After 5 weeks of a high fat diet in dogs, there was marked Na+ (> 500 mEq) retention and increased extracellular fluid volume. The Na+ retention was not due to renal vasoconstriction or decreased GFR, since GFR and renal plasma flow were elevated by 35-60%. We also found that the increased Na+ reabsorption caused a hypertensive shift of pressure natriuresis, indicating that elevated blood pressure is required to maintain a normal rate of Na+ excretion in obese dogs. The precise causes of increased tubular reabsorption and altered pressure natriuresis are not entirely clear, but roles for the renin-angiotensin and sympathetic nervous systems, insulin resistance and hyperinsulinemia, and altered intrarenal physical forces have been proposed.

          Obesity causes structural and functional changes in the renal medulla. In dogs fed a high fat diet for only 5-6 weeks, there are important changes in renal medullary histology, including increases in the number of interstitial cells and extracellular matrix between the tubules that appear to compress the tubules and vasa recta. The extracellular matrix stains with periodic acid-Schiff and Alcian blue, but not with oil red O, indicating that it is composed mainly of proteoglycans rather than lipids. We previously showed that total glycosaminoglycan content and the amount of hyaluronic acid, a major component of renal medullary extracellular matrix, were markedly increased in the inner medulla of obese compared with lean dogs, but not in the outer medulla or the cortex. We also found similar histologic changes in the renal medulla of obese humans. One consequence of these structural changes is compression of the renal medulla and increased renal interstitial fluid hydrostatic pressure. Because the kidney is surrounded by a tight capsule with low compliance, increased numbers of interstitial cells or extracellular matrix between the tubules could raise interstitial fluid hydrostatic and solid tissue pressures, causing compression of the tubules and blood vessels of the renal medulla.

          Obesity causes structural and functional changes in the glomerulus. Clinical studies have shown that obesity is often associated with microalbuminuria, and later proteinuria, even before major histologic changes or glomerulosclerosis occur in the kidneys. In the dog model of obesity, we observed significant histologic changes in the glomerulus after only 5-6 weeks of obesity, coincident with glomerular hyperfiltration and increased albumin excretion. There was visible enlargement of Bowman’s space, increased proliferating cell nuclear antigen (PCNA), (indicating proliferation of cells in the glomerulus), and increased glomerular TGF-. These early glomerular changes are likely to be precursors to the later development of proteinuria and glomerulosclerosis, but the mechanisms that initiate these changes are unknown.

Current Research - Mechanisms of Obesity Hypertension and Target Organ Injury
          Our studies indicate that activation of the sympathetic nervous system (SNS), via the renal nerves, and intrarenal structural changes play a major role in the pathophysiology of obesity hypertension. Our current studies are focused on the quantitative importance and mechanisms by which humoral systems activate the SNS and the role of neurohumoral and hemodynamic mechanisms in mediating biochemical and structural changes that occur in the kidneys, blood vessels, and heart in the early phases of obesity. We utilize models of dietary-induced obesity, produced by feeding a high fat diet in chronically instrumented dogs or rabbits, that closely mimic the neurohumoral, renal, and cardiovascular changes observed in obese humans.

          The major goals of our research are: 1) to test the hypothesis that systemic or CNS actions of leptin (a peptide secreted by adipocytes), angiotensin II (AngII), insulin, and non-esterified fatty acids (NEFA), acting individually or synergistically, increase renal sympathetic activity, impair renal excretory function, and raise arterial pressure in obesity; 2) to test the hypothesis that increased arterial pressure, increased sympathetic activity, AngII, and insulin interact to stimulate renal medullary matrix formation, glomerular injury, and other structural and biochemical changes in the kidneys, heart and blood vessels throughout the body in the early phases of obesity hypertension.

          Our laboratory utilizes an integrative approach, employing chronically instrumented dogs as well as biochemical, histological, and morphometric methods, as well as mathematical modelling to elucidate the role of neurohumoral mechanisms in the pathophysiology of obesity hypertension.

Further reading
          Hall, J.E. et. al. Mechanisms of obesity-induced hypertension. News in Physiological Sciences 11: 255-262, 1997.

          Hall, JE. Mechanisms of abnormal sodium handling in obesity hypertension. Am. J. Hypertension 10: 49S-44S. 1997.