Bone and the kidney: a systems biology approach to the molecular mechanisms of renal osteodystrophy

Despite its apparent static condition, the skeleton undergoes a permanent process of remodeling mediated by osteoblasts and osteoclasts. The activity of these cells is regulated by a plethora of factors, ranging from mechanical stress to the effects of hormones to the immune system. One well-studied regulatory system involves the maintenance of calcium homeostasis through a network whose main regulatory components include ionized calcium, phosphate, parathyroid hormone and active vitamin D. This system establishes the link between bone and kidney, as one of the kidney's endocrine functions is the activation of vitamin D, while electrolyte homeostasis is one of its excretory functions. Impaired renal function leads to disturbances in this regulatory system, resulting in the complex syndrome of renal osteodystrophy that affects the majority of patients with chronic renal failure. This review summarizes the current understanding of bone physiology on a molecular level, examines some of the pathological pathways related to renal disease, and concludes with an outlook on how the emerging field of systems biology may contribute to a more dynamic and quantitative understanding of the physiology and pathophysiology of renal bone disease.     

Study of Development of Function of Kidneys and Their Regulation on the Background of Pathological Process

By the example of reabsorption of sodium ions in kidney, it is shown that this process, alongside with establishment of the system of osmotic concentration, plays the key role in evolution of renal function. There is shown a similarity of tendencies of changes of the total sodium ion reabsorption in children’s kidney in the process of development and in a series of representatives of various vertebrate classes. An opposite tendency is revealed during the kidney dysfunction produced by chronic renal failure. At all stages of postnatal ontogenesis in healthy children and in adults, kidney maintains the same parameters of the blood serum ion composition and osmolality. A new approach to study evolution of functions is proposed, which is based on a combination of two L.A. Orbeli’s methods—ontogenetic and clinical, by the example of study of renal function and its regulation during development of a pathological process on the background of formation of function in postnatal ontogenesis. When using such approach in children with nocturnal enuresis, significance of autacoids in regulation of urine formation is established. In the case of acute pneumonia in children, a possibility of extrapituitary production of vasopressin-like substances in lungs is shown. In norm, in postnatal ontogenesis of healthy children, in regulation of renal functions and of diuresis system, effects of efferent nerves and hormones (vasopressin) dominate, while significance of autacoids is minimal. But at a dysfunction produced by a pathological process, a change of ratio of activities of these regulatory systems is revealed. The obtained data indicate importance of the clinical and experimental methods proposed by L.A. Orbeli in analysis of evolution of renal functions and study of the nature of regulations. A combination of several methods of evolutionary physiology in one study allows revealing new mechanisms underlying regulation of function and promotes formation of concepts about regularities of evolution of functions.__________Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 3, 2005, pp. 277–284.Original Russian Text Copyright © 2005 by Kuznetsova, Natochin.     

Human physiology: kidney

The content of human physiology as an independent part of current physiology is discussed. Substantiated is the point that subjects of human physiology are not only special sections of physiology where functions are inherent only in human (physiology of intellectual activity, speech, labor, sport), but also in peculiarities of functions, specificity of regulation of each of physiological systems. By the example of physiology of kidney and water-salt balance there are shown borders of norm, peculiarities of regulation in human, new chapters of renal physiology which have appeared in connection with achievements of molecular physiology.     

The role of taurine in renal disorders

This article examines the actions of taurine on models of renal dysfunction, the potential mechanisms of taurine action and the possible clinical significance of these findings. Our laboratory has written previously on the role of taurine in renal function and we have focused upon the normal physiology of the kidney and on the mechanisms and regulation of the renal transport of taurine. This review is a distinct change of emphasis in that we describe a number of studies which have evaluated various aspects of renal dysfunction, including hypertension and proteinuria, specific glomerular and tubular disorders, acute and chronic renal conditions, urinary tract conditions including infection and nephrolithiasis, and diabetic nephropathy. The subject of chronic kidney disease and renal transplantation will also be examined relative to β amino acid. The studies evaluated will be mainly recent ones, recognizing that older reviews of the role of this taurine in the kidney are available.     

The endocrine heart and natriuretic peptides: histochemistry, cell biology, and functional aspects of the renal urodilatin system

 This review focuses on some selected aspects of the endocrine heart and natriuretic peptides. The endocrine heart is composed of specific myoendocrine cells of the cardiac atria. The myoendocrine cells synthesize and secrete the natriuretic peptide hormones which exhibit natriuretic, diuretic, and vasorelaxant properties. Immunohistochemical analyses show that natriuretic peptides of the A-type and B-type are localized not only in the specific granules of these myoendocrine cells but also in many other organs including the brain, adrenal medulla, and kidney. Also, their receptors are detected in many organs showing the multiple functions of these regulatory peptides. Of the members of the natriuretic peptide family, ANP (ANP for atrial natriuretic peptide; also denominated cardiodilatin, CDD), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and the A-type, including its renal form, urodilatin, are emphasized in this review. Urodilatin is localized in the kidney, differentially processed, and secreted into the urine. The intrarenal synthesis and secretion is the basis for a paracrine system regulating water and sodium reabsorption at the level of the collecting duct. CDD/ANP-1-126, cleaved from a precursor of 126 amino acids in the heart to a 28-amino acid-containing circulating molecular form (CDD/ANP-99-126), and urodilatin (CDD/ANP-95-126) share similar biochemical features and biological functions, but urodilatin may be more involved in the regulation of body fluid volume and water–electrolyte excretion, while circulating CDD/ANP-99-126 is responsible for blood pressure regulation. The physiological and pharmacological properties of these peptides have great clinical impact, and as a consequence urodilatin is involved in drug development for the treatment of acute renal failure, cardiomyopathia, and acute asthma. Accepted: 8 July 1998     

Age-specific features in renal response to food intakes and training loads in young professional skiers

The age-specific features of renal functions have been studied in older adolescents and young adults training in ski racing before and after their water and food intake and training loads. Baseline renal functions in the morning demonstrated higher glomerular filtration rate (GFR) and more mature development of the osmoregulatory mechanisms (higher excretion of osmotically active substances, osmotic concentration index, and reabsorption of solute-free liquid) in young adults, compared with adolescents. After food intake, the osmoregulatory mechanisms provided in young adults an adequate renal response—increased excretion of ions in exchange for urea, which preserves osmolality. At the same time, increased excretion of osmotically active substances synchronously with growth in the rate of urine output, higher GFR and reabsorption of solute-free liquid was marked in adolescents, which points to less mature development of the osmoregulatory system. The similar trend of renal homeostatic responses after physical training indicated the activation of volume regulatory mechanisms which did not differ between age groups. Our conclusion is that the definitive volume regulation develops ahead of osmoregulation.     

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.     

Molecular regulation of NKCC2 in the thick ascending limb

The kidney plays an essential role in blood pressure regulation by controlling short-term and long-term NaCl and water balance. The thick ascending limb of the loop of Henle (TAL) reabsorbs 25-30% of the NaCl filtered by the glomeruli in a process mediated by the apical Na(+)-K(+)-2Cl(-) cotransporter NKCC2, which allows Na(+) and Cl(-) entry from the tubule lumen into TAL cells. In humans, mutations in the gene coding for NKCC2 result in decreased or absent activity characterized by severe salt and volume loss and decreased blood pressure (Bartter syndrome type 1). Opposite to Bartter's syndrome, enhanced NaCl absorption by the TAL is associated with human hypertension and animal models of salt-sensitive hypertension. TAL NaCl reabsorption is subject to exquisite control by hormones like vasopressin, parathyroid, glucagon, and adrenergic agonists (epinephrine and norepinephrine) that stimulate NaCl reabsorption. Atrial natriuretic peptides or autacoids like nitric oxide and prostaglandins inhibit NaCl reabsorption, promoting salt excretion. In general, the mechanism by which hormones control NaCl reabsorption is mediated directly or indirectly by altering the activity of NKCC2 in the TAL. Despite the importance of NKCC2 in renal physiology, the molecular mechanisms by which hormones, autacoids, physical factors, and intracellular ions regulate NKCC2 activity are largely unknown. During the last 5 years, it has become apparent that at least three molecular mechanisms determine NKCC2 activity. As such, membrane trafficking, phosphorylation, and protein-protein interactions have recently been described in TALs and heterologous expression systems as mechanisms that modulate NKCC2 activity. The focus of this review is to summarize recent data regarding NKCC2 regulation and discuss their potential implications in physiological control of TAL function, renal physiology, and blood pressure regulation.     

Lecture: New light on the role of claudins in the kidney

The physiology of paracellular permeation of ions and solutes in the kidney is pivotally important but poorly understood. Claudins are the key components of the paracellular pathway. Defects in claudin function result in a broad range of renal diseases, including hypomagnesemia, hypercalciuria and nephrolithiasis. This review describes recent findings on the physiological function of claudins underlying paracellular transport mechanisms with a focus on renal Ca ( 2+) handling. We have uncovered a molecular mechanism underlying paracellular Ca ( 2+) transport in the thick ascending limb of Henle (TAL) that involves the functional interplay of three important claudin genes: claudin-14, -16 and -19, all of which are associated with human kidney diseases with hypercalciuria, nephrolithiasis and bone mineral loss. The Ca ( 2+) sensing receptor (CaSR) signaling in the kidney has long been a mystery. By analyzing small non-coding RNA molecules in the kidney, we have uncovered a novel microRNA based signaling pathway downstream of CaSR that directly regulates claudin-14 gene expression and establishes the claudin-14 molecule as a key regulator for renal Ca ( 2+) homeostasis. The molecular cascade of CaSR-microRNAs-claudins forms a regulatory loop to maintain proper Ca ( 2+) homeostasis in the kidney.     

Assessment of renal function by the stable oxygen and hydrogen isotopes in human blood plasma

Water (H(2)O) is the most abundant and important molecule of life. Natural water contains small amount of heavy isotopes. Previously, few animal model studies have shown that the isotopic composition of body water could play important roles in physiology and pathophysiology. Here we study the stable isotopic ratios of hydrogen (δ(2)H) and oxygen (δ(18)O) in human blood plasma. The stable isotopic ratio is defined and determined by δ(sample) = [(R(sample)/R(STD))-1] * 1000, where R is the molar ratio of rare to abundant, for example, (18)O/(16)O. We observe that the δ(2)H and the δ(18)O in human blood plasma are associated with the human renal functions. The water isotope ratios of the δ(2)H and δ(18)O in human blood plasma of the control subjects are comparable to those of the diabetes subjects (with healthy kidney), but are statistically higher than those of the end stage renal disease subjects (p<0.001 for both ANOVA and Student's t-test). In addition, our data indicate the existence of the biological homeostasis of water isotopes in all subjects, except the end stage renal disease subjects under the haemodialysis treatment. Furthermore, the unexpected water contents (δ(2)H and δ(18)O) in blood plasma of body water may shed light on a novel assessment of renal functions.     

Purinergic signalling in the kidney in health and disease

The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine- and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.     

Human physiology: The kidney

The content of human physiology as an independent part of modern physiology is discussed. It is substantiated that not only special sections of physiology where functions are specific for humans (the physiology of intellectual activity, speech, labor, and sport), but also the characteristics of functions and the specificity of regulation of each of the physiological systems are subjects of human physiology. The boundaries of the norm, the characteristics of regulation in humans, new chapters of renal physiology that appeared due to the achievements of molecular physiology and require fundamentally new approaches are exemplified by the physiology of the kidneys and water-electrolyte balance.     

The role of insulin-like growth factors and IGF-binding proteins in the physiological and pathological processes of the kidney.

Insulin-like growth factors (IGFs) and their binding proteins are implicated in the growth regulation of the kidney during embryogenesis and differentiation. Recent evidence also suggests that IGFs play a role in kidney physiology (glomerular filtration rate, renal plasma flow) and pathology (diabetic renal hypertrophy, nephritis, glomerulosclerosis, kidney tumours, chronic renal failure). This review focuses on the biology of IGFs at the molecular, protein and receptor levels and considers their importance in renal physiology and pathology. The current data demonstrate a central role for the IGFs in the mediation of a wide variety of effects on renal growth, function and malignancy.     

Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors.

Carbonic anhydrase isozyme XII (CA XII) is a novel membrane-associated protein with a potential role in von Hippel-Lindau carcinogenesis. Although Northern blotting has revealed positive signal for CA XII in normal human kidney, this is the first study to demonstrate its cellular and subcellular localization along the human nephron and collecting duct. Immunohistochemistry with a polyclonal antibody (PAb) raised against truncated CA XII revealed distinct staining in the basolateral plasma membrane of the epithelial cells in the thick ascending limb of Henle and distal convoluted tubules, and in the principal cells of the collecting ducts. A weak basolateral signal was also detected in the epithelium of the proximal convoluted tubules. In addition to the normal kidney specimens, this immunohistochemical study included 31 renal tumors. CA XII showed moderate or strong plasma membrane-associated expression in most oncocytomas and clear-cell carcinomas. The segmental, cellular, and subcellular distribution of CA XII along the human nephron and collecting duct suggests that it may be one of the key enzymes involved in normal renal physiology, particularly in the regulation of water homeostasis. High expression of CA XII in some renal carcinomas may contribute to its role in von Hippel-Lindau carcinogenesis.     

Welcome to Organogenesis!

The physiology of paracellular permeation of ions and solutes in the kidney is pivotally important but poorly understood. Claudins are the key components of the paracellular pathway. Defects in claudin function result in a broad range of renal diseases, including hypomagnesemia, hypercalciuria and nephrolithiasis. This review describes recent findings on the physiological function of claudins underlying paracellular transport mechanisms with a focus on renal Ca²⁺ handling. We have uncovered a molecular mechanism underlying paracellular Ca²⁺ transport in the thick ascending limb of Henle (TAL) that involves the functional interplay of three important claudin genes: claudin-14, -16 and -19, all of which are associated with human kidney diseases with hypercalciuria, nephrolithiasis and bone mineral loss. The Ca²⁺ sensing receptor (CaSR) signaling in the kidney has long been a mystery. By analyzing small non-coding RNA molecules in the kidney, we have uncovered a novel microRNA based signaling pathway downstream of CaSR that directly regulates claudin-14 gene expression and establishes the claudin-14 molecule as a key regulator for renal Ca²⁺ homeostasis. The molecular cascade of CaSR-microRNAs-claudins forms a regulatory loop to maintain proper Ca²⁺ homeostasis in the kidney.     

Ectodomain shedding by ADAM proteases as a central regulator in kidney physiology and disease

Besides its involvement in blood and bone physiology, the kidney's main function is to filter substances and thereby regulate the electrolyte composition of body fluids, acid-base balance and toxin removal. Depending on underlying conditions, the nephron must undergo remodeling and cellular adaptations. The proteolytic removal of cell surface proteins via ectodomain shedding by A Disintegrin and Metalloproteases (ADAMs) is of importance for the regulation of cell-cell and cell-matrix adhesion of renal cells. ADAM10 controls glomerular and tubule development in a Notch1 signaling-dependent manner and regulates brush border composition. ADAM17 regulates the renin angiotensin system and is together with ADAM10 involved in calcium phosphate homeostasis. In kidney disease ADAMs, especially ADAM17 contribute to inflammation through their involvement in IL-6 trans-signaling, Notch-, epithelial growth factor receptor-, and tumor necrosis factor α signaling. ADAMs are interesting drug targets to reduce the inflammatory burden, defective cell adhesion and impaired signaling pathways in kidney diseases.