Electroneutral absorption of NaCl by the aldosterone-sensitive distal nephron: implication for normal electrolytes homeostasis and blood pressure regulation

Sodium absorption by the distal part of the nephron, i.e., the distal convoluted tubule, the connecting tubule, and the collecting duct, plays a major role in the control of homeostasis by the kidney. In this part of the nephron, sodium transport can either be electroneutral or electrogenic. The study of electrogenic Na⁺ absorption, which is mediated by the epithelial sodium channel (ENaC), has been the focus of considerable interest because of its implication in sodium, potassium, and acid–base homeostasis. However, recent studies have highlighted the crucial role played by electroneutral NaCl absorption in the regulation of the body content of sodium chloride, which in turn controls extracellular fluid volume and blood pressure. Here, we review the identification and characterization of the NaCl cotransporter (NCC), the molecule accounting for the main part of electroneutral NaCl absorption in the distal nephron, and its regulators. We also discuss recent work describing the identification of a novel “NCC-like” transport system mediated by pendrin and the sodium-driven chloride/bicarbonate exchanger (NDCBE) in the β-intercalated cells of the collecting system.     

WNK signalling pathways in blood pressure regulation

Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton’s hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure. There is a number of rare Mendelian blood pressure syndromes, which have shed light on the molecular mechanisms involved in dysregulated ion transport in the distal kidney. One in particular is Familial hyperkalemic hypertension (FHHt), an autosomal dominant monogenic form of hypertension characterised by high blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, and hypercalciuria. The clinical signs of FHHt are treated by low doses of thiazide diuretic, and it mirrors Gitelman syndrome which features the inverse phenotype of hypotension, hypokalemic metabolic alkalosis, and hypocalciuria. Gitelman syndrome is caused by loss of function mutations in the thiazide-sensitive Na/Cl cotransporter (NCC); however, FHHt patients do not have mutations in the SCL12A3 locus encoding NCC. Instead, mutations have been identified in genes that have revealed a key signalling pathway that regulates NCC and several other key transporters and ion channels in the kidney that are critical for BP regulation. This is the WNK kinase signalling pathway that is the subject of this review.     

How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?

Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes. Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1, Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the possibility that LS mutations may not simply exhibit dominant negative activity. Received 30 November 2006; received after revision 8 February 2007; accepted 13 March 2007     

Human progeroid syndromes,aging and cancer: new genetic and epigenetic insights into old questions

Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes. Received 28 July 2006; received after revision 5 September 2006; accepted 13 October 2006     

The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress

The RecQ family of DNA helicases is highly conserved throughout evolution and plays an important role in the maintenance of genomic stability in all organisms. Mutations in three of the five known family members in humans, BLM, WRN and RECQL4, give rise to disorders that are characterized by predisposition to cancer and premature aging, emphasizing the importance of studying the RecQ proteins and their cellular activities. Interestingly, three autosomal recessive disorders have been associated with mutations in the RECQL4 gene: Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes, thus making RECQL4 unique within the RecQ family of DNA helicases. To date, however, the molecular function of RECQL4 and the possible cellular pathways in which it is involved remain poorly understood. Here, we present an overview of recent findings in connection with RECQL4 and try to highlight different directions the field could head, helping to clarify the role of RECQL4 in preventing tumorigenesis and maintenance of genome integrity in humans. Received 31 October 2006; received after revision 4 January 2007; accepted 5 February 2007     

Sur l'origine des mucopolysaccharides acides du néphron, étudiée in vitro

Summary The tissue culture of renal explants proves that the acid mucopolysaccharides, previously described in the distal convolution and the collecting tubule, do not result from urinary colloid precipitation, but from local epithelial secretion. Their physiological significance is discussed.     

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

From a handful of uncloned genetic loci 6 years ago, great strides have been made in understanding the genetic and molecular aetiology of Bardet-Biedl syndrome (BBS), a rare pleiotropic disorder characterised by a multitude of symptoms, including obesity, retinal degeneration and cystic kidneys. Presently, 11 BBS genes have been cloned, with the likelihood that yet more BBS genes remain undiscovered. In 2003, a major breakthrough was made when it was shown that BBS is likely caused by defects in basal bodies and/or primary cilia. Since then, studies in numerous animal models of BBS have corroborated the initial findings and, in addition, have further refined the specific functions of BBS proteins. These include roles in establishing planar cell polarity (noncanonical Wnt signaling) in mice and zebrafish, modulating intraflagellar transport and lipid homeostasis in worms, and regulating intracellular trafficking and centrosomal functions in zebrafish and human tissue culture cells. From these discoveries, a common theme has emerged, namely that the primary function of BBS proteins may be to mediate and regulate microtubule-based intracellular transport processes. Received 20 April 2006; received after revision 30 May 2006; accepted 15 June 2006     

Reversal of net secretion to net absorption of potassium in rat large intestine by dietary potassium depletion

Feeding rats a diet low in potassium and high in sodium for 2 weeks led to a reversal of net potassium secretion to net potassium absorption in ligated segments of distal large intestine (colon descendens and rectum) under in-vivo conditions. This change in the direction of net potassium transport is probably important for the maintenance of potassium homeostasis.     

Evaluation of the anti-angiogenic effect of aloe-emodin

The present study identified aloe-emodin (AE, a hydroxyanthraquinone from Aloe vera and other plants) as a new anti-angiogenic compound with inhibitory effects in an in vivo angiogenesis assay and evaluates its effects on specific key steps of the angiogenic process. AE inhibits endothelial cell proliferation, but this effect is not cell specific, since AE also inhibits tumor cell proliferation. Cell migration and invasion are not remarkably affected by AE. On the other hand, AE has different effects on endothelial and tumor cell gelatinases. Two main targets of the pharmacological action of AE as an anti-angiogenic compound seem to be urokinase secretion and tubule formation of endothelial cells. Finally, AE produces a remarkable photocytotoxic effect on tumor cells. Taken together, our data indicate that AE can behave both as an anti-tumor and an anti-angiogenic compound and suggest that AE could be a candidate drug for photodynamic therapy. Received 7 September 2006; received after revision 17 October 2006; accepted 31 October 2006     

Reversal of net secretion to net absorption of potassium in rat large intestine by dietary potassium depletion

Summary Feeding rats a diet low in potassium and high in sodium for 2 weeks led to a reversal of net potassium secretion to net potassium absorption in ligated segments of distal large intestine (colon descendens and rectum) under in-vivo conditions. This change in the direction of net potassium transport is probably important for the maintenance of potassium homeostasis.The technical assistance of Mrs U. Seeliger is gratefully acknowledged.     

Focal and segmental glomerulosclerosis

An increasing cause of end-stage renal disease is the pathological lesion focal and segmental glomerulosclerosis (FSGS). FSGS is characterized by proteinuria and frequently nephrotic syndrome with ensuing renal failure. The etiology remains unknown in the majority of individuals. The idiopathic form of FSGS is most common; however, secondary forms of FSGS do exist. There is a form of FSGS that is fulminant that frequently recurs after renal transplantation with an estimated frequency of approximately 30%, suggesting that the pathogenesis is not solely a result of intrinsic kidney disease. Recently, hereditary forms of the disease were recognized as well as those associated with other congenital syndromes. Known genetic causes of the hereditary form of this disease have been suggested to account for upwards of 18% of cases. This review will address recent discoveries of the genetic mechanisms of hereditary FSGS and the current interpretations of their interactions at the slit diaphragm. Received 17 April 2006; received after revision 23 May 2006; accepted 6 July 2006     

Streptozotocin induced diabetic nephropathy and renal tumors in the rat

Summary Adult Wistar rats rendered diabetic by a single dose of streptozotocin develop renal morphological changes which show subtle differences compared to those seen in human diabetic renal disease. The early tubular degeneration is sited in the distal rather than the proximal convoluted tubule and subsequent glomerular lesion shows linear deposits of IgG and albumin in the basement membrane rather than in the mesangium. The carcinogenicity of streptozotocin in the rat is reconfirmed.Acknowledgements. We wish to thank Mr S.G. Watkins and Mrs D. Greening for technical assistance.     

Glycoprotein IIb/IIIa antagonists - from bench to practice

The central role played by the α_IIbβ₃ receptor in platelet aggregation, and hence in platelet thrombosis, has led to the development of a number of parenteral and oral glycoprotein (GP) IIb/IIIa inhibitors for use in cardiovascular disease states, such as acute coronary syndromes and stroke. The predominant effect of these agents is to inhibit platelet aggregation, although studies of α_IIbβ₃ receptor function and various GP IIb/IIIa inhibitors have demonstrated the potential for these agents to produce effects on other aspects of platelet function, in addition to non-platelet effects. Overall, clinical studies have demonstrated an impressive beneficial effect for parenteral agents in reducing ischemic complications following percutaneous intervention, and a more modest beneficial effect in the treatment of patients with acute coronary syndromes. Trials with oral GP IIb/IIIa inhibitors in similar patient populations have demonstrated toxicity, manifested by an increased mortality in treated patients. Increased understanding of molecular aspects of both α_IIbβ₃ receptor function and the effects of GP IIb/IIIa inhibition may help explain some of the inconsistency in recently reported clinical studies with parenteral agents, and the frank toxicity of oral agents. Such studies may also hold the key to the development of newer agents with enhanced therapeutic benefit. Received 10 September 2001; received after revision 22 October 2001; accepted 2 November 2001     

Curcumin: From ancient medicine to current clinical trials

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.     

Aneuploidy in the normal and diseased brain

The brain is remarkable for its complex organization and functions, which have been historically assumed to arise from cells with identical genomes. However, recent studies have shown that the brain is in fact a complex genetic mosaic of aneuploid and euploid cells. The precise function of neural aneuploidy and mosaicism are currently being examined on multiple fronts that include contributions to cellular diversity, cellular signaling and diseases of the central nervous system (CNS). Constitutive aneuploidy in genetic diseases has proven roles in brain dysfunction, as observed in Down syndrome (trisomy 21) and mosaic variegated aneuploidy. The existence of aneuploid cells within normal individuals raises the possibility that these cells might have distinct functions in the normal and diseased brain, the latter contributing to sporadic CNS disorders including cancer. Here we review what is known about neural aneuploidy, and offer speculations on its role in diseases of the brain. Received 13 April 2006; received after revision 2 June 2006; accepted 13 July 2006     

Oncogenic mechanisms in myeloproliferative disorders

Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms. Received 9 June 2006; received after revision 28 July 2006; accepted 11 September 2006     

Ethanol impairs Rho GTPase signaling and differentiation of cerebellar granule neurons in a rodent model of fetal alcohol syndrome

Developmental exposure to ethanol impairs fetal brain development and causes fetal alcohol syndrome. Although the cerebellum is one of the most alcohol-sensitive brain areas, signaling mechanisms underlying the deleterious effects of ethanol on developing cerebellar granule neurons (CGNs) are largely unknown. Here we describe the effects of in vivo ethanol exposure on neurite formation in CGNs and on the activation of Rho GTPases (RhoA and Rac1), regulators of neurite formation. Exposure of 7-day-old rat pups to ethanol for 3 h moderately increased blood alcohol concentration (BAC) (∼40 mM) and inhibited neurite formation and Rac1 activation in CGNs. Longer exposure to ethanol for 5 h resulted in higher BAC (∼80 mM), induced apoptosis, inhibited Rac1, and activated RhoA. Studies demonstrated a regulatory role of Rho GTPases in differentiation of cerebellar neurons, and indicated that ethanol-associated impairment of Rho GTPase signaling might contribute to brain defects observed in fetal alcohol syndrome. Received 16 July 2006; received after revision 12 September 2006; accepted 13 October 2006     

Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain

In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling. This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%, or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT) expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion, cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh homeostasis. Received 4 May 2006; received after revision 13 June 2006; accepted 20 June 2006     

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

Molecular determinants of antimalarial drug resistance are useful and informative tools that complement phenotypic assays for drug resistance. They also guide the design of strategies to circumvent such resistance once it has reached levels of clinical significance. Established resistance to arylaminoalcohols such as mefloquine and lumefantrine in SE Asia is mediated primarily by gene amplification of the P. falciparum drug transporter, pfmdr1. Single nucleotide polymorphisms in pfmdr1, whether assessed in field isolates or transfection experiments, are associated with changes in IC₅₀ values (to arylaminoalcohols and chloroquine), but not of such magnitude as to influence clinical treatment outcomes. Recently described emerging in vitro resistance to artemisinins in certain areas correlates with mutations in the SERCA-like sequence PfATP6 and supports PfATP6 as a key target for artemisinins. Received 13 February 2006; revised after revision 7 March 2006; accepted 29 March 2006     

Receptor communication within the lymphocyte plasma membrane: a role for the thrombospondin family of matricellular proteins

Lymphocytes, the principal cells of the immune system, carry out immune surveillance throughout the body by their unique capacity to constantly reposition themselves between a free-floating vascular state and a tissue state characterized by migration and frequent adhesive interactions with endothelial cells and components of the extracellular matrix. Therefore, mechanisms co-ordinating adhesion and migration with signals delivered through antigen recognition probably play a pivotal role for the regulation of lymphocyte behaviour and function. Endogenous thrombospondin-1 (TSP-1) seems to be the hub in such a mechanism for autocrine regulation of T cell adhesion and migration. TSP-1 functions as a mediator of cis interaction of vital receptors within the T lymphocyte plasma membrane, including integrins, low density lipoprotein receptor-related protein, calreticulin and integrin-associated protein. Received 1 June 2006; received after revision 28 June 2006; accepted 11 October 2006