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Insights into Salt Handling, Water Balance, and Blood Pressure Regulation by the Kidneys

Two studies in mice have shed light on the complex relationships between kidney physiology, salt intake, water balance, and hypertension. One of the kidney’s critical functions is to achieve electrolyte balance in the body by controlling urine salt concentration and water retention. Impairment of this essential function can lead to hypertension (high blood pressure). Two recent reports explored the links between salt, hypertension, and kidney function using rodent model systems.

Scientists have long believed that the body removes excess dietary salt through urination, leading to water loss that must be replenished—in other words, eating salty foods makes people thirsty. Recently, however, research has cast doubt on this simple relationship between salt and water consumption. In one previous study in 10 men, researchers found, surprisingly, that over time, increased salt consumption was associated with reduced water intake. In the present study, the team of researchers tested their previous observation experimentally using male mice that were fed either a low-salt diet with water or a high-salt diet with saline (salted water). Mice consuming a high-salt diet excreted more concentrated sodium in their urine than did mice on the lower-salt diet. Interestingly, over time the mice on a high-salt diet drank less fluid, retained more water, and consumed more food than did mice on a low-salt diet.

These results raised an important question: how does the body remove excess salt without simultaneously expelling too much water? The scientists considered that urea, a biological chemical abundantly found in urine, could be a key factor because urea in the kidney is known to drive reabsorption of water from developing urine. They found that the kidneys of mice on a high-salt diet contained higher levels of urea compared with those on a low-salt diet, helping to explain the observed water retention. Further examination of the mice revealed that additional urea was produced by muscle and liver tissue in response to increased salt. The muscle tissue appeared to be breaking down some of its molecular components as fuel to generate energy, likely to compensate for the energy-intensive process of urea production. This need for additional energy could also help explain the increased appetite observed in mice fed a high-salt diet. Together, these results uncover a novel coordinated, energy-intensive response to dietary salt by the liver, muscles, and kidneys to elevate urea levels, thereby conserving water.

In a separate study, scientists sought to gain a better understanding of the molecular basis of water maintenance and blood pressure regulation by the kidney. A segment of the nephron (the basic functional unit of the kidney) called the collecting duct fine-tunes the amounts of various essential substances, such as sodium, that can be retained in the body or excreted into the developing urine. The protein angiotensin II was previously shown to control water reabsorption in the collecting duct. To better understand angiotensin II’s role in the kidney, the researchers genetically engineered mice to lack the gene encoding the type 1 angiotensin (AT1) receptor, its essential protein partner, specifically in the collecting ducts. AT1 receptor-deficient mice had the same blood pressure as normal mice, and both groups experienced hypertension similarly when they were fed high-salt diets. Mice were then administered angiotensin II, which is also known to induce hypertension. Blood pressure in normal mice predictably increased, but surprisingly, blood pressure in AT1 receptor-deficient mice rose even higher; this finding was unexpected because elimination of AT1 receptors was expected to prevent angiotensin II’s ability to raise blood pressure. These AT1 receptor-deficient mice excreted less sodium than did normal mice when given angiotensin II, suggesting that the higher salt levels may have been responsible for the elevated blood pressure. The researchers then asked whether cyclooxygenase-2 (COX-2), a known regulator of angiotensin II function, was affected by AT1 receptor deficiency. Drugs that inhibit COX-2 function have been shown to influence blood pressure, leading the scientists to ask whether there could be a link between COX-2 and AT1 receptor activity in this segment of the kidney. They examined collecting ducts, and found that those of normal mice given angiotensin II contained higher levels of COX-2 than did their untreated counterparts, but the absence of AT1 receptors attenuated this response. Finally, the scientists again treated mice with angiotensin II to induce hypertension, but also administered a chemical inhibitor of COX-2 function. The COX-2 inhibitor eliminated the difference between AT1 receptor-deficient mice and normal mice, allowing the blood pressures of both groups to rise to similar levels, further implicating COX-2 as a mediator of angiotensin II-induced hypertension. Taken together, these results define a surprising, novel role in the collecting duct for the angiotensin II-AT1 receptor-COX-2 molecular pathway as a regulator of blood pressure.

These studies in mice challenge long-standing views and reveal the complexity of the kidney’s role in salt and water balance, and in blood pressure regulation. If the molecular pathways described are found to work similarly in people, these two studies could pave the way for a more detailed understanding of how the human body maintains water balance in response to salt intake, and could generate novel therapeutic approaches for reducing the risk of hypertension.


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