scholarly journals Glucagon actions on the kidney revisited: possible role in potassium homeostasis

2016 ◽  
Vol 311 (2) ◽  
pp. F469-F486 ◽  
Author(s):  
Lise Bankir ◽  
Nadine Bouby ◽  
Bertrand Blondeau ◽  
Gilles Crambert
Keyword(s):  
Collecting Duct ◽  
Distal Tubule ◽  
Glucagon Secretion ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Receptor Antagonists ◽  
Renal Handling ◽  
Glucagon Receptor ◽  
Potassium Homeostasis ◽  
Treatment Of Diabetes

It is now recognized that the metabolic disorders observed in diabetes are not, or not only due to the lack of insulin or insulin resistance, but also to elevated glucagon secretion. Accordingly, selective glucagon receptor antagonists are now proposed as a novel strategy for the treatment of diabetes. However, besides its metabolic actions, glucagon also influences kidney function. The glucagon receptor is expressed in the thick ascending limb, distal tubule, and collecting duct, and glucagon regulates the transepithelial transport of several solutes in these nephron segments. Moreover, it also influences solute transport in the proximal tubule, possibly by an indirect mechanism. This review summarizes the knowledge accumulated over the last 30 years about the influence of glucagon on the renal handling of electrolytes and urea. It also describes a possible novel role of glucagon in the short-term regulation of potassium homeostasis. Several original findings suggest that pancreatic α-cells may express a “potassium sensor” sensitive to changes in plasma K concentration and could respond by adapting glucagon secretion that, in turn, would regulate urinary K excretion. By their combined actions, glucagon and insulin, working in a combinatory mode, could ensure an independent regulation of both plasma glucose and plasma K concentrations. The results and hypotheses reviewed here suggest that the use of glucagon receptor antagonists for the treatment of diabetes should take into account their potential consequences on electrolyte handling by the kidney.

Ontogeny of the extracellular calcium-sensing receptor in rat kidney

1996 ◽  
Vol 271 (3) ◽  
pp. F736-F743 ◽  
Author(s):  
N. Chattopadhyay ◽  
M. Baum ◽  
M. Bai ◽  
D. Riccardi ◽  
S. C. Hebert ◽  
...  
Keyword(s):  
Renal Function ◽  
Divalent Cations ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Distal Tubule ◽  
Perinatal Period ◽  
Postnatal Period ◽  
Thick Ascending Limb ◽  
Renal Handling ◽  
Ureteric Buds

We recently cloned extracellular Ca(2+)-sensing receptors (CaRs) from bovine parathyroid and rat kidney that play key roles in Ca2+ homeostasis. Inactivating mutations of the CaR in the inherited human disorder, familial hypocalciuric hypercalcemia, cause reduced responsiveness of the parathyroid to extracellular Ca2+ (Cao2+), as well as abnormally avid renal tubular reabsorption of both Ca2+ and Mg2+ in the distal tubule, suggesting an important role for the CaR in regulating parathyroid hormone (PTH) secretion and renal handling of divalent cations. High Cao2+ also inhibits vasopressinstimulated adenosine 3',5'-cyclic monophosphate accumulation in the medullary thick ascending limb (MTAL) and water reabsorption in the collecting duct (CD) and modulates various other aspects of renal function. The relevance of the CaR to these processes, however, is uncertain. Reduced responsiveness of vasopressin-and PTH-mediated actions on the kidney have been described in the newborn that could potentially reflect effects of the CaR on these aspects of renal function. To define further the role of the CaR in regulating renal function, including the above-mentioned changes during the perinatal period, therefore, we have studied its ontogeny in rat kidney. Northern and Western blot analyses, as well as immunohistochemistry with CaR-specific probes, demonstrate that there is little prenatal expression of the extracellular Ca(2+)-sensing receptor, except in large tubules and branching ureteric buds of developing nephrons. Postnatally, CaR mRNA and protein increase markedly during the 1st wk, related principally to expression of the receptor in the developing TAL and, to a lesser extent, in the CD. The level of expression of the receptor remains nearly constant after postnatal day 14. These results demonstrate that the perinatal increases in expression of CaR mRNA and protein parallel its tissue-specific renal expression. Furthermore, it is possible that some of the previously described changes in renal handling of divalent cations and water in the perinatal and immediate postnatal period are related, in part, to the increasing levels of expression of the CaR and resultant inhibitory effects on the actions of PTH and antidiuretic hormone on the developing nephron.

Abnormal postpartum renal development and cystogenesis in the bcl-2 (-/-) mouse

1996 ◽  
Vol 271 (1) ◽  
pp. F184-F193 ◽  
Author(s):  
C. M. Sorenson ◽  
B. J. Padanilam ◽  
M. R. Hammerman
Keyword(s):  
Cellular Proliferation ◽  
Kidney Development ◽  
Apoptotic Cell ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Renal Development ◽  
Thick Ascending Limb ◽  
Renal Hypoplasia ◽  
Cellular Origin ◽  
Bax Protein

Mice deficient for B cell leukemia/lymphoma gene 2 [bcl-2(-/-) mice] manifest congenital renal hypoplasia and develop multicystic kidney disease and renal failure postnatally. To characterize postpartum renal development, to identify the cellular origin of the cysts, and to provide insight into the role that bcl-2 deficiency plays in the cystogenic process, we examined the morphology of kidneys from bcl-2 (-/-) mice and wild-type littermates [bcl-2 (+/+)] from birth (P0) to postpartum day 28 (P28), determined whether abnormalities of cellular proliferation and apoptosis accompany cyst development, and characterized expression of the bcl-2-related protein, bax. Between P0 and P7, kidneys from bcl-2 (-/-) and bcl-2 (+/+) mice undergo a comparable increase in weight and have similar histological appearances. However, during the next 2 wk of life, weight gain in kidneys from bcl-2 (-/-) mice is reduced compared with that in kidneys from bcl-2 (+/+) animals, and cysts develop in tubules with staining characteristics of proximal tubule, distal tubule/medullary thick ascending limb of Henle's loop, and collecting duct. Unaffected glomeruli and proximal tubules in kidneys of bcl-2 (-/-) mice undergo compensatory growth. Cystogenesis is accompanied by enhanced incorporation of 5-bromo-2'-deoxyuridine in cells within cortex and medulla and apoptosis of cells within cysts and in the renal interstitium. Bax protein is expressed in the distal tubule in kidneys of bcl-2 (+/+) and bcl-2 (-/-) mice and in some, but not all cysts. We conclude that abnormal regulation of DNA synthesis and apoptosis accompany cystogenesis in bcl-2 (-/-) mice during postpartum kidney development. Continued expression of bax could enhance apoptotic cell death.0

scholarly journals Differential Expression Patterns of Claudins, Tight Junction Membrane Proteins, in Mouse Nephron Segments

2002 ◽  
Vol 13 (4) ◽  
pp. 875-886 ◽  
Author(s):  
Yumiko Kiuchi-Saishin ◽  
Shimpei Gotoh ◽  
Mikio Furuse ◽  
Akiko Takasuga ◽  
Yasuo Tano ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Tight Junction ◽  
Polyclonal Antibodies ◽  
Collecting Duct ◽  
Expression Patterns ◽  
Distal Tubule ◽  
Northern Blotting ◽  
Thick Ascending Limb ◽  
Specific Expression ◽  
Nephron Segments

ABSTRACT. As the first step in understanding the physiologic functions of claudins (tight junction integral membrane proteins) in nephrons, the expression of claudin-1 to -16 in mouse kidneys was examined by Northern blotting. Among these claudins, only claudin-6, -9, -13, and -14 were not detectable. Claudin-5 and -15 were detected only in endothelial cells. Polyclonal antibodies specific for claudin-7 and -12 were not available. Therefore, the distributions of claudin-1, -2, -3, -4, -8, -10, -11, and -16 in nephron segments were examined with immunofluorescence microscopy. For identification of individual segments, antibodies specific for segment markers were used. Immunofluorescence microscopic analyses of serial frozen sections of mouse kidneys with polyclonal antibodies for claudins and segment markers revealed that claudins demonstrated very complicated, segment-specific, expression patterns in nephrons, i.e., claudin-1 and -2 in Bowman’s capsule, claudin-2, -10, and -11 in the proximal tubule, claudin-2 in the thin descending limb of Henle, claudin-3, -4, and -8 in the thin ascending limb of Henle, claudin-3, -10, -11, and -16 in the thick ascending limb of Henle, claudin-3 and -8 in the distal tubule, and claudin-3, -4, and -8 in the collecting duct. These segment-specific expression patterns of claudins are discussed, with special reference to the physiologic functions of tight junctions in nephrons.

Regional and segmental localization of AE2 anion exchanger mRNA and protein in rat kidney

1995 ◽  
Vol 269 (4) ◽  
pp. F461-F468 ◽  
Author(s):  
F. C. Brosius ◽  
K. Nguyen ◽  
A. K. Stuart-Tilley ◽  
C. Haller ◽  
J. P. Briggs ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Rat Kidney ◽  
Chloride Concentration ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Base Exchange ◽  
Medullary Thick Ascending Limb ◽  
Nephron Segment ◽  
Medullary Collecting Duct

Chloride/base exchange activity has been detected in every mammalian nephron segment in which it has been sought. However, in contrast to the Cl-/HCO3- exchanger AE1 in type A intercalated cells, localization of AE2 within the kidney has not been reported. We therefore studied AE2 expression in rat kidney. AE2 mRNA was present in cortex, outer medulla, and inner medulla. Semiquantitative polymerase chain reaction of cDNA from microdissected tubules revealed AE2 cDNA levels as follows [copies of cDNA derived per mm tubule (+/- SE)]: proximal convoluted tubule, 688 +/- 161; proximal straight tubule, 652 +/- 189; medullary thick ascending limb, 1,378 +/- 226; cortical thick ascending limb, 741 +/- 24; cortical collecting duct, 909 +/- 71; and outer medullary collecting duct, 579 +/- 132. AE2 cDNA was also amplified in thin limbs and in inner medullary collecting duct. AE2 polypeptide was detected in all kidney regions. AE2 mRNA and protein were also detected in several renal cell lines. The data are compatible with the postulated roles of AE2 in maintenance of intracellular pH and chloride concentration and with its possible participation in transepithelial transport.

scholarly journals Regulation of calcium reabsorption along the rat nephron: a modeling study

2015 ◽  
Vol 308 (6) ◽  
pp. F553-F566 ◽  
Author(s):  
Aurélie Edwards
Keyword(s):  
Transient Receptor Potential ◽  
Stone Formation ◽  
Collecting Duct ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Calcium Sensing ◽  
The Impact

We expanded a mathematical model of transepithelial transport along the rat nephron to include the transport of Ca2+ and probe the impact of calcium-sensing mechanisms on Ca2+ reabsorption. The model nephron extends from the medullary thick ascending limb (mTAL) to the inner medullary collecting duct (IMCD). Our model reproduces several experimental findings, such as measurements of luminal Ca2+ concentrations in cortical tubules, and the effects of furosemide or deletion of the transient receptor potential channel vanilloid subtype 5 (TRPV5) on urinary Ca2+ excretion. In vitro microperfusion of rat TAL has demonstrated that activation of the calcium-sensing receptor CaSR lowers the TAL permeability to Ca2+, PCaTAL (Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P. J Clin Invest 122: 3355, 2012). Our results suggest that this regulatory mechanism significantly impacts renal Ca2+ handling: when plasma Ca2+ concentration ([Ca2+]) is raised by 10%, the CaSR-mediated reduction in PCaTAL per se is predicted to enhance urinary Ca2+ excretion by ∼30%. If high [Ca2+] also induces renal outer medullary potassium (ROMK) inhibition, urinary Ca2+ excretion is further raised. In vitro, increases in luminal [Ca2+] have been shown to activate H+-ATPase pumps in the outer medullary CD and to lower the water permeability of IMCD. Our model suggests that if these responses exhibit the sigmoidal dependence on luminal [Ca2+] that is characteristic of CaSR, then the impact of elevated Ca2+ levels in the CD on urinary volume and pH remains limited. Finally, our model suggests that CaSR inhibitors could significantly reduce urinary Ca2+ excretion in hypoparathyroidism, thereby reducing the risk of calcium stone formation.

Structural-functional relationships along the distal nephron

1986 ◽  
Vol 250 (1) ◽  
pp. F1-F15 ◽  
Author(s):  
K. M. Madsen ◽  
C. C. Tisher
Keyword(s):  
Atpase Activity ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Distal Tubule ◽  
Structural Heterogeneity ◽  
Apical Plasma Membrane ◽  
Thick Ascending Limb ◽  
Intercalated Cells ◽  
Principal Cells ◽  
Functional Relationships

The distal tubule, which includes the thick ascending limb (TAL), the macula densa, and the distal convoluted tubule (DCT), and the collecting duct are structurally heterogeneous, thus reflecting the functional heterogeneity that is also present. As the TAL ascends from medulla to cortex, the surface area of the apical plasma membrane increases while that of the basolateral membrane decreases. The structure of the DCT resembles that of the medullary TAL. An excellent correlation exists between structure, Na-K-ATPase activity, and NaCl reabsorptive capacity in the distal tubule. The collecting duct is subdivided into the initial collecting tubule (ICT), and cortical (CCD), outer medullary (OMCD), and inner medullary (IMCD) collecting ducts. Between the distal tubule and the collecting duct is a transition region termed the connecting segment or connecting tubule (CNT). Considerable structural heterogeneity exists along the collecting duct within the two major cell populations, the intercalated cells and the principal cells. In the CNT, the ICT, and the CCD, potassium loading and mineralocorticoids stimulate Na-K-ATPase activity and cause proliferation of the basolateral membrane of CNT cells and principal cells, thus identifying the cells responsible for mineralocorticoid-stimulated potassium secretion in these regions. Finally, at least two morphologically distinct populations of intercalated cells exist, types A and B. In the rat, type A predominates in the CNT and the OMCD and is believed to be responsible for H+ secretion, at least in the OMCD. Type B predominates in the CCD, where it may be involved in bicarbonate secretion.

scholarly journals In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

2010 ◽  
Vol 299 (6) ◽  
pp. F1473-F1485 ◽  
Author(s):  
Daniel Ackermann ◽  
Nikolay Gresko ◽  
Monique Carrel ◽  
Dominique Loffing-Cueni ◽  
Daniel Habermehl ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Glucocorticoid Receptors ◽  
Nuclear Translocation ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Distal Tubule ◽  
Plasma Aldosterone ◽  
Thick Ascending Limb ◽  
Cell Nuclei

Aldosterone and corticosterone bind to mineralocorticoid (MR) and glucocorticoid receptors (GR), which, upon ligand binding, are thought to translocate to the cell nucleus to act as transcription factors. Mineralocorticoid selectivity is achieved by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that inactivates 11β-hydroxy glucocorticoids. High expression levels of 11β-HSD2 characterize the aldosterone-sensitive distal nephron (ASDN), which comprises the segment-specific cells of late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). We used MR- and GR-specific antibodies to study localization and regulation of MR and GR in kidneys of rats with altered plasma aldosterone and corticosterone levels. In control rats, MR and GR were found in cell nuclei of thick ascending limb (TAL), DCT, CNT, CD cells, and intercalated cells (IC). GR was also abundant in cell nuclei and the subapical compartment of proximal tubule (PT) cells. Dietary NaCl loading, which lowers plasma aldosterone, caused a selective removal of GR from cell nuclei of 11β-HSD2-positive ASDN. The nuclear localization of MR was unaffected. Adrenalectomy (ADX) resulted in removal of MR and GR from the cell nuclei of all epithelial cells. Aldosterone replacement rapidly relocated the receptors in the cell nuclei. In ASDN cells, low-dose corticosterone replacement caused nuclear localization of MR, but not of GR. The GR was redistributed to the nucleus only in PT, TAL, early DCT, and IC that express no or very little 11β-HSD2. In ASDN cells, nuclear GR localization was only achieved when corticosterone was replaced at high doses. Thus ligand-induced nuclear translocation of MR and GR are part of MR and GR regulation in the kidney and show remarkable segment- and cell type-specific characteristics. Differential regulation of MR and GR may alter the level of heterodimerization of the receptors and hence may contribute to the complexity of corticosteroid effects on ASDN function.

Localization of kallikrein in the rat kidney and its anatomical relationship to renin.

1982 ◽  
Vol 30 (4) ◽  
pp. 385-390 ◽  
Author(s):  
T B Orstavvik ◽  
T Inagami
Keyword(s):  
Collecting Duct ◽  
Rat Kidney ◽  
Distal Tubule ◽  
Juxtaglomerular Apparatus ◽  
Thick Ascending Limb ◽  
Loop Of Henle ◽  
Afferent Arteriole ◽  
Epitheloid Cells ◽  
Anatomical Relationship

The anatomical relationship between kallikrein and renin in the rat kidney was investigated immunohistochemically by the peroxidase-antiperoxidase method. Kallikrein was localized to the convoluted distal tubule, starting at a point, distal to the juxtaglomerular apparatus, where the thick ascending limb of loop of Henle transformed into the convoluted distal tubule. The thick ascending limb was identified by its content of uromucoid (Tamm-Horsfall glycoprotein). Kallikrein was never observed within the juxtaglomerular apparatus itself. The kallikrein-containing tubule ended where the distal tubule submerged into the collecting duct. Renin was found in epitheloid cells of the afferent arteriole. When neighboring sections were stained for kallikrein and renin, respectively, no close anatomical relationship was observed between the kallikrein-containing and the renin-containing structures.

Immunolocalization of ectonucleotidases along the rat nephron

2006 ◽  
Vol 290 (2) ◽  
pp. F550-F560 ◽  
Author(s):  
Renu M. Vekaria ◽  
David G. Shirley ◽  
Jean Sévigny ◽  
Robert J. Unwin
Keyword(s):  
Collecting Duct ◽  
Distal Tubule ◽  
Extracellular Nucleotides ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Low Level ◽  
Amplification Method ◽  
Sprague Dawley Rats ◽  
Collecting Ducts ◽  
Calbindin D

Evidence is accumulating that extracellular nucleotides act as autocrine/paracrine agents in most tissues, including the kidneys. Several families of surface-located enzymes, collectively known as ectonucleotidases, can degrade nucleotides. Using immunohistochemistry, we have examined the segmental distribution of five ectonucleotidases along the rat nephron. Perfusion-fixed kidneys were obtained from anesthetized male Sprague-Dawley rats. Cryostat sections of cortical and medullary regions were incubated with antibodies specific to the following enzymes: ectonucleoside triphosphate diphosphohydrolase (NTPDase) 1, NTPDase2, NTPDase3, ectonucleotide pyrophosphatase phosphodiesterase 3 (NPP3), and ecto-5′-nucleotidase. Sections were then costained with Phaseolus vulgaris erythroagglutinin (for identification of proximal tubules) and antibodies against Tamm-Horsfall protein (for identification of thick ascending limb), calbindin-D28k (for identification of distal tubule), and aquaporin-2 (for identification of collecting duct). The tyramide signal amplification method was used when the ectonucleotidase and marker antibody were raised in the same species. The glomerulus expressed NTPDase1 and NPP3. The proximal tubule showed prominent expression of NPP3 and ecto-5′-nucleotidase in most, but not all, segments. NTPDase2 and NTPDase3, but not NPP3 or ecto-5′-nucleotidase, were expressed in the thick ascending limb and distal tubule. NTPDase3, with some low-level expression of ecto-5′-nucleotidase, was also found in cortical and outer medullary collecting ducts. Inner medullary collecting ducts displayed low-level staining for NTPDase1, NTPDase2, NTPDase3, and ecto-5′-nucleotidase. We conclude that these ectonucleotidases are differentially expressed along the nephron and may play a key role in activation of purinoceptors by nucleotides and nucleosides.

Juxtamedullary nephrons during acute metabolic alkalosis in the rat

1985 ◽  
Vol 249 (1) ◽  
pp. F107-F116
Author(s):  
J. P. Frommer ◽  
D. E. Wesson ◽  
M. E. Laski ◽  
N. A. Kurtzman
Keyword(s):  
Metabolic Alkalosis ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Fractional Excretion ◽  
Group Iv ◽  
Renal Handling ◽  
Group Iii ◽  
Contralateral Kidney ◽  
Group I ◽  
Papillary Collecting Duct

The renal handling of bicarbonate during acute metabolic alkalosis was examined in Munich-Wistar rats using micropuncture techniques. Group I received an acute bicarbonate load, and fractional delivery of total CO2 (tCO2) (FDtCO2) to the superficial late distal tubule (LD) was significantly lower than to the base of the papillary collecting duct (B) (18.4 +/- 1.7 vs. 22.9 +/- 1.5%; P less than 0.01), indicating net addition of bicarbonate between LD and B. When acutely bicarbonate-loaded rats had their deep nephrons destroyed with bromoethylamine hydrobromide (BEA) (group II), net addition of tCO2 between LD and B was abolished and net reabsorption uncovered (FDtCO2 LD: 28.0 +/- 3.6 vs. B: 17.5 +/- 2.5%; P less than 0.01). The infusion of amiloride (2.5 mg/kg body wt) to alkalotic rats treated with BEA (group III) completely inhibited distal bicarbonate reabsorption but did not reestablish addition (FDtCO2 LD: 27.6 +/- 1.6 vs. B: 26.1 +/- 3.7%; P = NS). The values obtained for sham-operated animals (group IV) were the same for group I. The patterns that were observed between LD and B were reproduced for the four groups of animals when FDtCO2 LD was compared with the fractional excretion of bicarbonate in the urine of the intact contralateral kidney. These studies suggest that juxtamedullary nephrons contribute a higher load of bicarbonate than superficial nephrons to the final urine during acute metabolic alkalosis in the rat.

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