The Integral Role of Chloride & With-No-Lysine Kinases in Cell Volume Regulation & Hypertension.

Chloride anions are the most abundant in humans. For many years, it has been believed that chloride is simply a counterion of all other cations, ensuring the electroneutrality of the extracellular space. Recent data suggests that chloride anions possess a broad spectrum of important activities that regulate vital cellular functions. It is now evident that, apart from its contribution to the electroneutrality of the extracellular space, it acts as an osmole and contributes to extracellular and intracellular volume regulation. Its anionic charge also contributes to the generation of cell membrane potential. The most interesting action of chloride anions is their ability to regulate the activity of with-no-lysine kinases, which in turn regulate the activity of sodium chloride and potassium chloride cotransporters and govern the reabsorption of salt and excretion of potassium by nephron epithelia. Chloride anions seem to play a crucial role in cell functions, such as cell volume regulation, sodium reabsorption in the distal nephron, potassium balance, and sodium sensitivity, which lead to hypertension. All of these functions are accomplished on a molecular level via complicated metabolic pathways, many of which remain poorly defined. We attempted to elucidate some of these pathways in light of recent advances in our knowledge, obtained mainly from experimental studies.

Molecular pathophysiology of Bartter's and Gitelman's syndromes.

BACKGROUND: In the last two decades, progress in cytogenetic and genome research has enabled investigators to unravel the underlying molecular mechanisms of inherited tubulopathies such as Bartter's and Gitelman's syndromes and helped physicians to better understand not only these two pathologic entities but also renal pathophysiology and salt sensitive hypertension. DATA SOURCES: Articles collected from PubMed and open access journals included original articles, research articles, and comprehensive reviews. They were evaluated by the authors with an special emphasis on originality and up to date information about molecular pathophysiology. RESULTS: Bartter's and Gitelman's syndromes are two different inherited salt loosing tubulopathies. They are characterized by various inability of distal nephron to reabsorb sodium chloride with resultant extarcellular volume contraction and increased activity of the renin angiotensin aldosterone system. Hypokalemic metabolic alkalosis is a common feature of these two forms of tubulopathies. Hypercalciuria characterizes the majority of Bartter's syndrome, and hypomagnesemia with hypocalciuria characterizes Gitelman's syndrome. Low blood pressure is a common feature among patients who suffered from these tubulopathies. Bartter's syndromes encompass a heterogeneous group of ion channels defects localized at the thick ascending limp of Henle's loop with resultant loss of function of sodium-potassium-2 chloride cotransporter. These defects result in the impairment of the countercurrent multiplication system of the kidney as well as calcium, potassium and acid base disturbances which in the majority of cases are proved lethal especially in the antenatal and/or immediate postnatal life period. The underlying pathology in Gitelman's syndrome is defined to the distal convoluted tubule and is related to loss of function of the sodium-chloride cotransporter. The results of this defect encompass the inability of extracellular volume homeostasis, magnesium and potassium conservation, and acid base disturbances which are generally mild and in the majority of cases are not life-threatening. CONCLUSIONS: Recent advances in molecular pathophysiology of Bartter's and Gitelman's syndromes have helped physicians to better understand the underlying mechanisms of these pathologic entities which remain obscure. Data collected from experiments among genetically manipulated animals enable us to better understand the pathophysiology of mammalian kidney and the underlying mechanisms of salt sensitive hypertension and to lay a foundation for the future development of new drugs, especially diuretics and antihypertensive drugs.

The loop of Henle as the milestone of mammalian kindey concentrating ability: a historical review.

The first description of the renal tubules is attributed to Lorenzo Bellini in 1662 and four years later Marcello Malpighi described the glomerulus. In 1842 Sir William Bowman described the capsule that surrounds the Malpighian body and its connection with the renal tubule and introduced the "excretory" hypothesis of urine formation. In the same year, Carl Ludwig introduced the "filtration-reabsorption" hypothesis of urine formation. Bowman's hypothesis was accepted by the so-called "vitalists" and Ludwig's hypothesis by the so-called "mechanists". In the middle of this confliction, Jacob Henle described in 1862 the homonymous "U" shaped loop but his discovery has neglected. In 1942 Werner Kuhn, a physical chemist, proposed that the loop of Henle may be the natural analog of the hairpin countercurrent multiplication system which concentrates urine in mammalian kidneys. In 1951 Kuhn, Hargitay and Wirz showed experimentally that the loop of Henle was the most important part of the countercurrent multiplication system of urine-concentrating mechanism in mammalian kidneys. The new theory was accepted by English-speaking scientists later, in 1958, when Carl Gottschalk and Margaret Mylle published their experimental work and proved that Kuhn's theory was correct. Gottschalk summarized the evidence of the accumulated knowledge in 1962, three centuries after the first description of renal tubules and one century after description of Henle's loop.

Metabolic syndrome risk factors and estimated glomerular filtration rate among children and adolescents.

The aim of this study was to seek the possible relationship between estimated glomerular filtration rate (e-GFR) and anthropometric indexes, lipids, insulin sensitivity, and metabolic syndrome risk factors among healthy children and adolescents. Sufficient evidence suggest that obesity is related with a novel form of glomerulopathy named obesity-related glomerulopathy (ORG) among adults, children, and adolescents. Glomerular filtration rate was estimated from serum creatinine in 166 healthy children and adolescents [79 males, 87 females; age 10.6 +/- 3.3 (3-18) years]. Anthropometric indexes and systolic and diastolic blood pressure were measured. Fasting insulin, glucose, creatinine, uric acid, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglycerides were estimated. Insulin sensitivity was estimated from known formulas. The presence of certain metabolic syndrome risk factors was checked among the studied population. Boys showed higher e-GFR rates than girls (f = 8.49, p = 0.004). We found a strong positive correlation between e-GFR and body weight (r = 0.415), body mass index (BMI) (r = 0.28), waist circumference (r = 0.419), hip circumference (r = 0.364), birth weight (r = 0.164), systolic blood pressure (SBP) (r = 0.305), and mean arterial pressure (MAP) (r = 0.207). A negative correlation was found between e-GFR and fasting glucose (r = -0.19), total cholesterol (r = -0.27) and LDL-cholesterol (r = -0.26). Clustering of metabolic syndrome risk factors among certain individuals was correlated with higher e-GFR rates (f = 3.606, p = 0.007). The results of this study suggest that gender, anthropometric indexes, and SBP are strong positive determinants of e-GFR among children and adolescents. Waist circumference is the most powerful determinant of e-GFR. Fasting glucose and lipid abnormalities are negative determinants of e-GFR among the studied population. Clustering of metabolic syndrome risk factors is coupled with higher e-GFR rates.

Insulin and human obesity.

The prevalence of obesity among modern communities increases dramatically and trends to achieve the characteristics of an epidemic. Obesity is the result of a sedentary life style and increased food intake, which characterises western communities. Obesity is closely related to insulin resistance and hyperinsulinemia and the very frequent combination of obesity and NIDDM is characterised as "Diabesity". The behaviour of man in seeking food and the amount of food consumption is a complicated situation, which is regulated by the CNS and especially in the arcuate nucleus of the hypothalamus. A repertoire of neurohormonal actions, generated in peripheral tissues and integrated in the CNS, encompasses many peptides with orexigenic and anorexigenic actions. Two main hormones, insulin and leptin, accomplish the fine-tuning of these peptides action at the critical level of body weight and energy control. The high prevalence of insulin resistance and hyperinsulinemia in obesity indicates a causative relationship between these two situations. It seems likely that insulin resistance in muscle cells is the prime "defect" which renders individuals vulnerable to obesity. The high prevalence of insulin resistance, about 25%, among otherwise healthy subjects indicates that this genetically determined "defect" may be the result of an evolutionary selection which rendered mankind capable of surviving during long periods of famine, in his long journey from the hunter-gatherer period of his life to the present time of plenty.