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Gordon Syndrome (GS) is a rare familial hypertension syndrome with a characteristic hyperkalaemia which distinguishes it from other syndromic forms of hypertension that typically cause hypokalaemia. Patients with GS respond to aggressive salt-restriction or relatively small doses of thiazide diuretics, which suggests that activation of the thiazide-sensitive Na/Cl cotransporter (NCC) in the distal nephron is to blame. However, the mechanism has proved to be complex. In 2001, mutations in genes encoding two serine/threonine kinases, WNK1 and WNK4, were identified as causing GS. However, it took several years to appreciate that these kinases operated in a cascade with downstream serine/threonine kinases (SPAK and OSR1) actually phosphorylating and activating NCC and the closely related cotransporters NKCC1 and NKCC2. The hyperkalaemia in GS arises from an independent action of WNK1/WNK4 to reduce cell-surface expression of ROMK, the secretory K-channel in the collecting ducts. However, mutations in WNK1/4 are present in a small minority of GS families, and further genes have emerged ( CUL3 and KLHL3) that code for Cullin-3 (a scaffold protein in an ubiquitin-E3 ligase) and an adaptor protein, Kelch3, respectively. These new players regulate the ubiquitination and proteasomal degradation of WNK kinases, thereby adding to the complex picture we now have of NCC regulation in the distal nephron. [ABSTRACT FROM AUTHOR]

The kidney continuously adapts daily renal excretion of NaCl to match dietary intakes in order to maintain the NaCl content of the body, and keep vascular volume constant. Any situation that leads to NaCl retention favors a rise in blood pressure. The aldosterone-sensitive distal nephron, which contains two main types of cells, principal (PC) and intercalated (IC) cells, is an important site for the final regulation of urinary Na excretion. Research over the past 20 years established a paradigm in which PCs are the exclusive site of Na absorption while ICs are solely dedicated to acid-base transport. Recent studies have revealed the unexpected importance of ICs for NaCl reabsorption. Here, we review the mechanisms of Na and Cl transport in the aldosterone-sensitive distal nephron, with emphasis on the role of ICs in maintaining NaCl balance and normal blood pressure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The amiloride-sensitive epithelial sodium channel (ENaC) has previously been shown to be involved in the maintenance of body fluid volume and in Na+ absorption across the skin and urinary bladder in amphibians. However, the function and distribution of ENaC have not been clearly described in amphibian kidney. We therefore cloned the ENaC α-subunit cDNA from kidney of the marine toad, Bufo marinus. The ENaC mRNA and protein were abundantly expressed in the kidney and in the urinary bladder and ventral pelvic skin. In an immunohistochemical study, the ENaC α-subunit protein was specifically localized to the apical membrane of the principal cells but not the intercalated cells from the late distal tubule to the collecting duct in the kidney or in the apical area of cells of urinary bladder epithelia. When toads were acclimated to dry and hyper-saline environments, the levels of ENaC mRNA expression in the kidney and urinary bladder decreased under hyper-saline acclimation, but not under dry conditions. Immunohistochemical observations indicated that the levels of ENaC protein expression were much lower in the apical area of renal distal tubules and urinary bladder epithelia of hyper-saline acclimated toad compared with controls. The present study suggests that Bufo ENaC is significantly expressed and functions during Na+ reabsorption in the apical membrane domain in the distal nephron of normal and desiccated toads. Natriuresis may be caused by decreases in ENaC expression and its trafficking to the cell surface in the distal nephron, a response to prevent excessive Na+ reabsorption in hyper-saline-acclimated toads. [ABSTRACT FROM AUTHOR]

Kinins are vasoactive paracrine peptides which participate in a wide range of functions, including the regulation of local organ blood flow, systemic blood pressure, transepithelial water and electrolyte transport, cellular growth, capillary permeability and inflammatory response, and pain. The recent introduction of specific bradykinin receptor subtype antagonists has greatly advanced our understanding of the role of the kallikrein-kinin system (KKS) in various physiological and disease states. However, a major gap remains in our knowledge of the role of kinins in early development. In this review, evidence is presented that the developing nephron expresses both tissue kallikrein and kininogen, and that the genes encoding the components of the KKS are subject to considerable developmental regulation. The activity of the intrarenal kinin-generating system is lowest in the developing kidney and increases with age. Completion of nephrogenesis is characterized by a marked surge in intrarenal kallikrein synthesis and gene transcription. Maturation is associated with redistribution of intrarenal kallikrein and its messenger RNA from the inner to outer cortical nephrons following the centrifugal pattern of nephron development. Challenges for the future include delineation of the direct role of kinins in the maturation of renal functions and elucidation of the molecular mechanisms underlying the developmental expression of the KKS. [ABSTRACT FROM AUTHOR]

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In acute interstitial nephritis (AIN), mononuclear cells invade the tubules (tubulitis). The segmental localization of tubulitis is not precisely known. To clarify this question, formalin-fixed kidney biopsy specimens from 13 patients with AIN were studied stereologically by identifying cortical tubules with segment-specific markers. The periodic acid-Schiff reaction, peanut lectin, and antibodies against Tamm-Horsfall protein and epidermal cytokeratins all applied to the same section were used to identify the proximal tubules (PTs), distal convoluted tubules, distal straight tubules, and the cortical collecting system (connecting tubules and cortical collecting ducts), respectively. Morphometrically, an estimate of the relative volume of the inflammatory cell infiltrates within each category of tubular segments was obtained. Inflammatory cells were infrequently found in PTs (1.2%) but were frequently localized in distal tubules and the cortical collecting system (7.6%). There was no difference in the amount of the inflammatory cell infiltrate within these segments. Re-examination of an electron microscopic study of AIN carried out in this laboratory revealed that mononuclear cells were rarely seen in convoluted PTs but were frequently observed in straight PTs and all segments distal to them. The observations indicate that it is the distal nephron which is primarily affected by inflammatory cell infiltration in AIN. [ABSTRACT FROM AUTHOR]

The sites of outflux ofCa along the nephron were investigated using microinfusion technique in acutely thyroparathyroidectomized (TPTX), intact and TPTX Wistar rats substituted with parathyroid hormone (PTH). In all three groupsCa outflux occurred along the proximal tubule, the loop of Henle and along the distal tubule. After microinfusion into late distal tubulesCa recovery in ipsilateral urine was essentially complete for the TPTX group but was only 83 and 65% for the intact and the PTH substituted animals. Increases in microinfusion flow rate from 2-20 nl/min into early and middle distal tubules resulted in increased urinary recovery ofCa for all three groups. Similarily, increases in microinfusate Ca concentration from 0.2-2.0 and 5.0 mmol/l resulted in increased fractional urinary recovery ofCa both in the presence and absence of PTH. WhenCa andH inulin containing solutions were continuously microinfused into early distal tubules for one hour periods an anticalciuric effect of PTH could be demonstrated. It is concluded that Ca, in addition to its outflux in the proximal tubule and in the loop of Henle, is reabsorbed in the distal tubule accessible to micropuncture. PTH acts anticalciuric at this latter site. [ABSTRACT FROM AUTHOR]

To characterize the Ca transport process across the apical membrane of the rabbit connecting tubule (CNT), we examined the effects of luminal pressure on parathyroid hormone (PTH)-dependent apical Ca transport in this segment perfused in vitro. An increase of perfusion pressure (0.2 to 1.2 KPa) caused cytoplasmic free Ca concentration ([Ca].) to increase by 42 ± 11 n m in Fura-2 loaded perfused CNT. The response was accentuated when 10 n m PTH was added to the bath (101 ± 30 n m, n = 6). Addition of 0.1 m m chlorphenylthio-cAMP (CPT-cAMP) to the bath also augmented the [Ca]; response to pressure from 36 ± 16 to 84 ± 26 n m ( n = 3). Under steady perfusion pressure at 1.2 KPa, PTH (10 n m) increased [Ca]; by 31 ± 7 n m ( n = 5), whereas it did only slightly by 6 ± 2 n m ( n = 12) at 0.2 KPa. The pressure-dependent increase of [Ca]; was abolished by removing luminal Ca ( n = 3), and was not affected by 0.1 and 10 μ m nicardipine ( n = 4) in the presence of 10 n m PTH. Cell-attached patch clamp studies on the apical membrane of everted CNT with pipettes filled with either 200 m m CaCl or 140 m m NaCl revealed channel activities with conductances of 42 ± 2 pS ( n = 4) or 173 ± 7 pS ( n = 5), respectively. An application of negative pressure (−4.9 KPa) to the patch pipette augmented its mean number of open channels ( NP) from 0.005 ± 0.001 to 0.022 ± 0.005 in the Ca-filled pipette, and was further accelerated to 0.085 ± 0.014 ( n = 3) by 0.1 m m CPT-cAMP. In the Na-filled pipette, similar results were obtained ( n = 3), and CPT-cAMP did not activate the stretch-activated channel in the absence of negative pressure ( n = 3). These results suggest that a stretch-activated nonselective cation channel exists in the apical membrane of the CNT and that it is activated by PTH in the presence of hydrostatic pressure, allowing entry of Ca transport from the apical membrane. [ABSTRACT FROM AUTHOR]

ROMK1 is an inwardly rectifying K+ channel cloned from the outer medulla of rat kidney. We have determined the permeation and blocking characteristics for several monovalent cations in ROMK1 when expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. The selectivity sequence for monovalent cations as determined by reversal potential changes under bi-ionic conditions was K+ > Rb+ > Cs+ = NH4+ >> Na+ = Li+. The conductivity for the two permeant ions K+ and Rb+ was a saturable function of the external concentration, with Km values of 11.5 ± 1.3 mmol l–1 ( n = 19) and 47.3 ± 4.8 mmol l–1 ( n = 19), respectively. With mixtures of K+ and Rb+, the conductance went through a clear minimum as the concentration ratio [Rb]/[K+Rb] was varied between 0 and 1. ROMK1 was blocked by both Cs+ and Ba2+ in a concentration- and voltage-dependent manner. The electrical distance (δ) at which Ba2+ and Cs+ blocked the channel was 0.41 and 0.69, respectively, suggesting that these two ions block at different sites within the pore. Taken together with previous reports, the results indicate that ROMK1 has a multi-ion pore, and that the N-terminus contributes to the pore structure. [ABSTRACT FROM AUTHOR]