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Homeostasis can be defined as the maintenance of a constant internal environment within an organism, whether unicellular or multicellular. Sufficient cellular function can only be maintained within a narrow range of conditions, thereby validating the undeniable significance of homeostatic mechanisms in life. The concept of homeostasis was first pioneered in the 19th century by the French physiologist Claude Bernard. He famously stated in 1857 that “La fixité du milieu intérieur est la condition de la vie libre”, which can be translated as “the constancy of the internal environment is necessary for free life” . Light can be shed on the underlying meaning of this maxim by comparing an organism with a wide array of sensitive and efficient homeostatic mechanisms, to one with none whatsoever. Whilst the latter can only inhabit an environment in which the external conditions are relatively constant, the former can exploit many more environments- hence Bernard’s “vie libre”, or “free life”- due to its ability to maintain a constant internal environment.

The mammalian kidney plays a pivotal role in maintaining homeostasis. This organ mediates not just one, but several aspects of homeostasis , including the excretion of certain metabolites and excess water and ions; the regulation of electrolyte concentration in the plasma and interstitial fluid; osmoregulation; the control of blood pressure; the maintenance of an equilibrium in pH; erythropoeisis, the process by which red blood cells are produced; and glucose homeostasis. Consequently, the kidney is of vital importance to the survival and efficient functioning of cells. Its role in maintaining the constancy of such a large number of conditions suggests the need to understand the kidney’s profound role in the body. As a result, this essay will focus on the ways, and associated mechanisms, in which the kidney aids in the regulation a constant internal environment.

To begin, the kidney is crucial in the excretion of excess water, ions and waste products, such as urea, uric acid and creatinine. The removal of excess water and ions is required to ensure that the solute potential (ψs) of interstitial fluid, the fluid that perfuses the tissues in the body, and of the plasma, remain relatively constant. Fluctuations of the solute potential of the tissue fluid can result in too many water molecules moving by osmosis either into or out of cells across their cell surface membranes, thus causing osmotic damage. More specifically, the former scenario, caused by hypotonic interstitial fluid, can lead to cell lysis , whereas the latter, which is induced by a hypertonic fluid, can lead to crenation3. In order to understand the intricacies of this filtration and excretion process, an overview of the anatomy of the kidney is first necessary.

Much of the urea, creatinine and uric acid are removed from the blood by ultrafiltration at the Malpighian body. Some creatinine is actively secreted into the lumen of the proximal convoluted tubule. The excretion of these metabolites is vital to keep the sufficient functioning of cells. Hyperuricemia, or elevated levels of serum uric acid, can lead to diseases such as gout, and is often associated to the Lesch-Nyhan syndrome . This problem is compounded by the fact that humans and other primates lack the enzyme urate oxidase, which is responsible for the breakdown of uric acid . The excretion of urea is required to maintain nitrogen equilibrium, which can be off-set by an excess intake of protein in the diet. Urea, CO(NH2)2, is synthesised in the liver in two stages: first, the deamination of amino acids to produce ammonia, and second, the use of this ammonia in the ornithine cycle to form urea. In an adult human, approximately 30g of urea is synthesised every day on an average diet , thus illustrating the importance of excreting this large amount of substance. Moreover, several substances are secreted by the distal convoluted tubule, including ammonia, hydrogen (H+) ions and penicillin.

The kidney’s role in the control of osmotic pressure in the body is of undeniable significance. For one, maintaining a constant water potential of tissue fluid prevents osmotic damage to cells, either by cell lysis or crenation. Further, a constant osmotic pressure maintains a constant hydrostatic pressure in the blood; it also ensures that the tissues are perfused by a sufficient volume of interstitial fluid, whilst preventing oedema. As the amount of water determines the concentration of ions and other substances in the interstitial fluid, it is crucial to regulate the concentration of water molecules in order to ensure the efficient function of cells. In addition, it preserves the necessary concentration gradients required for the efficient transport of ions across the phospholipid bilayer of cell membranes by the various intrinsic proteins. Electrolyte balance is essential as the relative concentrations of the different types of cations and anions in both intracellular and extracellular fluid is necessary for the execution of many essential processes. For example, the intracellular and extracellular concentrations of Na+ and K+ ions is significant in neurones, as they play a vital role in the establishment of resting potentials, and for depolarisation and subsequent repolarisation. Sufficient water is necessary as it is also a metabolite: it plays a crucial role in many reactions and pathways, such as respiration and hydrolysis (for example, of glycogen and proteins). In addition, a suitable amount of water is necessary due to its ability to act as an effective temperature buffer to the body, on account of its relatively high specific heat capacity.

When an increase in the plasma osmolarity is detected by the osmoreceptors, AVP is secreted from the posterior pituitary gland into the blood. Once it reaches the kidney, the hormone induces a markedly enhanced permeability of the collecting ducts and the distal convoluted tubule to water. AVP achieves this by activating the receptor V2 , a subtype of vasopressin receptor that is exclusively expressed in the kidney, found on the basolateral membrane of the tubular cells. Upon activation, the action of AVP is mediated by cyclic AMP (cAMP), which acts as the secondary messenger33. Cyclic AMP is synthesised from ATP via the enzyme adenylyl cyclase, which is in turn activated by G-proteins coupled to the V2 receptors. The subsequent cAMP cascade (achieved through the activation of protein kinase A) results in aquaporin-2 (AQP 2) found in storage vesicles in the cell to be inserted into the apical membrane by exocytosis . In addition, the activity of urea transporter A1 (UT-A1) in the inner medullary collecting ducts is stimulated by the action of AVP . This causes urea to diffuse into the medullary interstitium, thereby raising its concentration in the area and rendering the interstitial fluid even more hypertonic. As a result, the efflux of water down the osmotic gradient is further enhanced. The ameliorated diffusion of water down an osmotic gradient and into the bloodstream brings about a decrease in the osmotic pressure of the plasma. This is detected by the osmoreceptors, which causes secretion of AVP to be inhibited. Similarly, in response to an unusually low plasma osmotic pressure, AVP secretion by the posterior pituitary will be inhibited. The necessity of AVP and of the role it plays in the kidney can be best demonstrated by a condition in which the action or secretion of AVP is somehow interrupted: diabetes insipidus. Diabetes insipidus results in excessive thirst and production of copious amounts of dilute urine . The causes of this condition can vary; nephrogenic diabetes insipidus, for example, can be caused by a defect in the V2 receptor protein.

The maintenance of a constant blood pressure, which is closely associated with fluid balance, is equally essential to the survival of mammalian organisms. Hypotension, the condition where the arterial pressure is abnormally low, and hypertension, when the arterial pressure is abnormally high, can both have a significant impact on the body. The causes for these conditions are numerous, ranging from haemorrhage and desanguination (inducing a decrease in blood volume) for the former, to obesity, sleep apnea and high sodium content in the diet for the latter. In terms of capillary haemodynamics, the effects of an abnormal blood pressure are clear. Hypotension will result in the hydrostatic pressure at the arterial end being too low. Not only will the markedly lower hydrostatic pressure at the arterial end cause less tissue fluid to perfuse the cells, but also the effect of the oncotic pressure at the venous end will be far greater than usual. The result is that there is insufficient perfusion of the tissue by interstitial fluid, which in turn prevents efficient cellular function. Conversely, an abnormally high blood pressure results in a high hydrostatic pressure in the capillaries; as a result, interstitial fluid accumulates in the tissues, eventually causing oedema. In addition, the damage caused to capillary walls, and hence to organs that contain a large amount of capillaries, can create severe problems. Indeed, on a larger scale, hypertension can bring about stroke, heart failure and chronic renal disease.

The action of angiotensin II is not restricted to just the kidney. Amongst other effects, Ang II causes the secretion of AVP from the supraoptic region (found in mammalian brains) of the hypothalamus; is a potent dipsogen (stimulates the sensation of thirst) in an attempt to increase fluid volume; and results in the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH also induces an increase in aldosterone levels in the blood by direct action on glomerulosa cells . These mechanisms are designed to increase the fluid volume of the plasma in order to return blood pressure to normal levels. An understanding of the renin-angiotensin system has clear clinical significance. For example, the use of ACE inhibitors, such as Captopril, and of direct renin inhibitors, such as aliskiren, which obviates the binding of angiotensinogen to renin , are important ways in which hypertension can be treated.

The maintenance of a constant hematocrit, the proportion of the volume of blood that consists of erythrocytes (red blood cells), is a significant aspect of homeostasis that is, in part, regulated by the kidney. The production of erythrocytes in the bone marrow is mainly mediated by the hormone erythropoietin (EPO) , a protein that is mainly synthesised in the kidneys. Erythropoiesis, the process of producing mature red blood cells, is of great importance on account of the vital role erythrocytes play in mammals. Each red blood cell in circulation contains several molecules of haemoglobin, a metalloprotein consisting of four globular protein subunits (α and β chains) and a heme group, consisting of a central Fe2+ cation covalently bonded to a heterocyclic ring, porphyrin, which acts as a ligand. It is this molecule that is responsible for the transport of oxygen, the molecule crucial in aerobic respiration in cells, and more specifically as the final electron acceptor in oxidative phosphorylation in mitochondria. In areas where there is a high partial pressure of oxygen, namely the lungs, haemoglobin absorbs oxygen. By contrast, haemoglobin unloads oxygen where it is required: at respiring tissue, where there is a low partial pressure of O2 and a high partial pressure of CO2.

Upon the secretion of erythropoietin by the peritubular fibroblasts into systemic circulation, the hormone travels in the bloodstream until it reaches the bone marrow. EPO stimulates the production of mature erythrocytes by mediating the survival, proliferation and differentiation of unipotent erythroid progenitor cells , called erythroblasts. When EPO binds onto erythropoietin receptors in the bone marrow, the JAK2 (Janus Kinase 2) cascade is initiated, thereby protecting the erythroid progenitor cells from apoptosis . Thus, the viability of the erythroblasts is preserved, and this is of great importance because these progenitor cells are the precursors to the mature erythrocytes. Consequently, the erythroblast can undergo maturation. The progenitor cell loses its nucleus, and most of its intracellular membranes are degraded; the now non-nucleated form of the cell, termed a reticulocyte, then loses its ribosomes, thus preventing any further synthesis of haemoglobin . At this stage, the cell is an erythrocyte and can enter circulation. It is clear, therefore, that reduced EPO secretion can lead to anaemia. During chronic renal disease, EPO secretion is significantly surpressed. The application of genetic engineering and the use of recombinant DNA, however, have allowed the in vitro production of EPO, known as Human Recombinant EPO (rhEPO). rhEPO has shown great promise in treating and preventing anaemia in patients suffering from chronic renal disease.

The regulation of the concentration of glucose in the blood is of utmost importance. Glucose is used as an energy source in tissue, whereby it is used to produce ATP via aerobic or anaerobic respiration. In particular, the brain is highly dependent on glucose as its energy source, being an obligate glucose consumer; neuroglycopenia, the condition where there is an inadequate supply of glucose to the brain, can affect function and may even to lead to coma. This underlies the need to prevent hypoglycaemia. Furthermore, a change in the concentration of free glucose in circulation can have a marked effect on the water potential of the blood. This, in turn, can bring about an imbalance in the amount of water moving into or out of tissues by osmosis. In this sense, modulating glucose concentration is closely linked with osmoregulation, further outlining the importance of preventing hypo- and hyperglycaemia. Previously, the kidney is thought to have contributed to glucose homeostasis in a minor way. This observation has been based on evidence derived from experiments that have employed a “net balance” approach: by measuring the net uptake or release of glucose by a particular organ. The inherent flaw in employing this approach is that it does not take into account that glucose uptake and release may be occurring simultaneously; the two processes may be compartmentalised, so uptake and release may be occurring in different locations within the same organ and may be differentially mediated. Consequently, the “net balance” approach may tend to underestimate the contribution of an organ such as the kidney to glucose homeostasis.