Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11β-HSD activity

2010 ◽  
Vol 298 (5) ◽  
pp. F1178-F1187 ◽  
Author(s):  
Andrew S. Brem ◽  
David J. Morris ◽  
Yan Ge ◽  
Lance Dworkin ◽  
Evelyn Tolbert ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Tissue Growth ◽  
Proximal Tubule Cells ◽  
Ru 486 ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
Induced Changes ◽  
Rat Proximal Tubule ◽  
Sirius Red

Aldosterone (Aldo) can be a profibrotic factor in cardiovascular and renal tissues. This study tests the hypothesis that prolonged Aldo exposure is able to directly induce fibrotic changes in the kidney of a normal nonhypertensive animal. Immortalized rat proximal tubule cells (IRPTC) containing 11β-hydroxysteroid dehydrogenase (11β-HSD1) but no mineralocorticoid receptors (MR) and mouse inner medullary collecting duct cells (IMCD) containing 11β-HSD2 and MR were examined. IRPTC exposed to Aldo or corticosterone (10 nM) for 48 h demonstrated no change in collagen production as assessed by Sirius red staining. In contrast, IMCD treated with Aldo exhibited a marked increase in the expression of collagen, fibronectin, and connective tissue growth factor (CTGF), whereas corticosterone alone had no effect. The Aldo-induced overexperession of collagen, fibronectin, and CTGF was substantially attenuated by the MR antagonist RU-318 and by the 11β-HSD end product 11-dehydrocorticosterone, but not by the glucocorticoid receptor antagonist RU-486. In vivo, early fibrotic changes with elevated collagen, fibronectin, and CTGF expression were observed in kidneys isolated from normotensive adrenalectomized mice receiving a continuous infusion of Aldo (8 μg·kg−1·day−1) for 1 wk. These changes were not present in corticosterone-treated mice. Aldo-induced changes were attenuated in adrenally intact mice and in mice treated with RU-318 or 11-dehydrocorticosterone. Thus, extended Aldo exposure produces fibrotic changes in cells containing MR and in normal kidneys. MR antagonists and the end products of 11β-HSD attenuate these fibrogenic effects.

Urodilatin: binding properties and stimulation of cGMP generation in rat kidney cells

1993 ◽  
Vol 264 (2) ◽  
pp. F267-F273
Author(s):  
H. Saxenhofer ◽  
W. R. Fitzgibbon ◽  
R. V. Paul
Keyword(s):  
Guanylate Cyclase ◽  
Mesangial Cells ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Binding Characteristics ◽  
Papillary Collecting Duct ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
Anp Receptors

Urodilatin (URO) [ANP-(95-126)] is an analogue of atrial natriuretic peptide (alpha-ANP) [ANP-(99-126)] that was first isolated from human urine. In rat mesangial cells, URO competed with high affinity for non-guanylate cyclase-coupled ANPR-C receptors [concentration at which 50% labeled ligand is displaced (IC50) approximately 70 pM], but with lesser affinity to the guanylate cyclase-linked ANPR-A receptors (IC50 approximately 800 pM). alpha-ANP bound to both receptors with similar affinity [dissociation constant (Kd) approximately 150 pM]. In papillary collecting duct homogenates, which possess only ANPR-A receptors, the apparent Kd value averaged 229 pM for alpha-ANP and 2.7 nM for URO. Intravenous URO was at least as potent and effective as alpha-ANP in inducing diuresis and natriuresis in anesthetized rats, but URO was approximately 10-fold less potent in stimulating guanosine 3',5'-cyclic monophosphate generation in mesangial and inner medullary collecting duct cells. We conclude that URO has a lesser affinity than alpha-ANP for guanylate cyclase-coupled ANP receptors in the kidney and that the relative natriuretic potency of URO in vivo cannot be directly attributed to its binding characteristics with ANPR-A receptors.

scholarly journals The PPARδLigand GW501516 Reduces Growth but Not Apoptosis in Mouse Inner Medullary Collecting Duct Cells

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-11 ◽  
Author(s):  
Jordan Clark ◽  
Rania Nasrallah ◽  
Richard L. Hébert
Keyword(s):  
Caspase 3 ◽  
Collecting Duct ◽  
Renal Diseases ◽  
Growth Responses ◽  
Therapeutic Implications ◽  
Dna And Protein Synthesis ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
High Doses ◽  
Induced Changes

The collecting duct (CD) expresses considerable amounts of PPARδ. While its role is unknown in the CD, in other renal cells it has been shown to regulate both growth and apoptosis. We thus hypothesized that PPARδreduces apoptotic responses and stimulates cell growth in the mouse CD, and examined the effect of GW501516, a synthetic PPARδligand, on these responses in mouse IMCD-K2 cells. High doses of GW501516 decreased both DNA and protein synthesis in these cells by 80%, but had no overall effect on cell viability. Although anisomycin treatment resulted in an increase of caspase-3 levels of about 2.59-fold of control, GW501516 did not affect anisomycin-induced changes in active caspase-3 levels. These results show that a PPARδligand inhibits growth but does not affect anisomycin-apoptosis in a mouse IMCD cell line. This could have therapeutic implications for renal diseases associated with increased CD growth responses.

Inner medullary collecting duct Na(+)-H+ exchanger

1991 ◽  
Vol 260 (6) ◽  
pp. C1300-C1307 ◽  
Author(s):  
K. S. Hering-Smith ◽  
E. J. Cragoe ◽  
D. Weiner ◽  
L. L. Hamm
Keyword(s):  
Intracellular Ph ◽  
Collecting Duct ◽  
Cell Types ◽  
Opposite Polarity ◽  
Proximal Tubule Cells ◽  
Inner Medullary Collecting Duct ◽  
Medullary Collecting Duct ◽  
Renal Proximal Tubule Cells ◽  
Image Analysis Techniques

Cells from the inner medullary collecting duct (IMCD) exhibit Na(+)-H+ exchange. The present studies were performed to address certain important characteristics of this process in cultured IMCD cells. First, Na(+)-H+ exchange was found to be present both at 37 degrees C and at 25 degrees C, in contrast to Na(+)-independent H+ extrusion, which was only observed in some cultures and only at 37 degrees C. Second, with the use of image analysis techniques, virtually all cells in IMCD cultures were demonstrated to possess Na(+)-H+ exchange, whether or not the cells exhibited Na(+)-independent intracellular pH recovery from acid loads. Also, Na(+)-H+ exchange was found to be expressed on the basolateral aspect of these cells, but not on the apical membrane. These properties of IMCD Na(+)-H+ exchange are consistent with a function to regulate intracellular pH rather than mediate transepithelial acid-base transport. Na(+)-H+ exchange in IMCD cells was also compared with that in cultured renal proximal tubule cells. Despite physiologically distinct roles in vivo, Na(+)-H+ exchange in these two cell types in culture was found to be similar with respect to the Km for Na+ and the Ki for 5-(N-ethyl-N-isopropyl)amiloride. These data are consistent with functionally similar (if not identical) processes mediating Na(+)-H+ exchange in these two cell types, but with opposite polarity

HGF-mediated chemotaxis and tubulogenesis require activation of the phosphatidylinositol 3-kinase

1995 ◽  
Vol 268 (6) ◽  
pp. F1211-F1217 ◽  
Author(s):  
M. P. Derman ◽  
M. J. Cunha ◽  
E. J. Barros ◽  
S. K. Nigam ◽  
L. G. Cantley
Keyword(s):  
Collecting Duct ◽  
Collagen Matrix ◽  
Phosphatidylinositol 3 Kinase ◽  
Process Formation ◽  
High Affinity Receptor ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
Phosphatidylinositol 3

The association of hepatocyte growth factor (HGF) with its high-affinity receptor, c-met, has been shown to induce mitogenesis, motogenesis, and morphogenesis in renal epithelial cells (L. G. Cantley, E. J. G. Barros, M. Gandhi, M. Rauchman, and S. K. Nigam. Am. J. Physiol. 267 (Renal Fluid Electrolyte Physiol. 36): F271-F280, 1994), suggesting that HGF may be critical to the orchestration of both renal development and regeneration following injury. Although signal transduction pathways activated by c-met include the phosphatidylinositol 3-kinase (PI-3-kinase), phospholipase C gamma, ras, and others, the activation of PI-3-kinase has been the most striking in vivo. We therefore investigated whether the pathways that mediate phenotypic changes in inner medullary collecting duct cells are altered by inhibition of PI-3-kinase with the fungal metabolite, wortmannin. In these cells, the mean inhibitory concentration for in vitro wortmannin inhibition of PI-3-kinase was approximately 0.2 nM. At this low concentration, motogenesis (quantified by chemotaxis) and morphogenesis (by branching-process formation within collagen matrix) were inhibited in a striking and parallel fashion, while mitogenesis was inhibited to a lesser degree. These experiments suggest that activation of PI-3-kinase is critical for c-met-mediated chemotaxis and tubulogenesis.

Acidification adaptation in cultured inner medullary collecting duct cells

1993 ◽  
Vol 264 (5) ◽  
pp. F765-F769 ◽  
Author(s):  
R. Mankus ◽  
J. H. Schwartz ◽  
E. A. Alexander
Keyword(s):  
Lucifer Yellow ◽  
Collecting Duct ◽  
C Cells ◽  
Inner Medullary Collecting Duct ◽  
Pump Activity ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
New Protein

Chronic acid feeding stimulates the rat inner medullary collecting duct (IMCD) to increase acid secretion in vivo (acidification adaptation), but the mechanism for this phenomenon is unknown. Our purpose was to determine whether IMCD cells undergo adaptation in vitro and to explore the mechanism of this response. Confluent cultured rat IMCD cells were exposed to incubation media supplemented with 10(-7) M deoxycorticosterone acetate, pH 7.0 [acid incubated (AI)] or 7.7 [control (C)], for 48 h, and cell pH (pHi) was determined using 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Resting pHi was 7.46 +/- 0.05 for AI and 7.25 +/- 0.04 for C (P < 0.05). N-ethylmaleimide-sensitive pHi recovery after an acute acid pulse was 0.030 +/- 0.002 for AI and 0.020 +/- 0.002 pH U/min for C (P < 0.05). However, when AI and C cells were incubated with 7 x 10(-6) M cycloheximide, the increment in pHi and enhanced proton pump activity was abolished. In addition, exocytic function, as measured by Lucifer yellow release, was increased significantly in AI cells. In summary, incubation of IMCD cells in acid medium stimulates acidification adaptation by a mechanism dependent on new protein synthesis.

Kinins inhibit conductive Na+ uptake by rabbit inner medullary collecting duct cells

1990 ◽  
Vol 258 (6) ◽  
pp. F1584-F1591 ◽  
Author(s):  
M. L. Zeidel ◽  
K. Jabs ◽  
D. Kikeri ◽  
P. Silva
Keyword(s):  
Initial Rate ◽  
Collecting Duct ◽  
Physiological Effect ◽  
Na Transport ◽  
Inner Medullary Collecting Duct ◽  
Transport Effects ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
Na Uptake

Kinins promote natriuresis in vivo, at least in part by altering Na+ transport in the collecting duct. Using freshly prepared suspensions of rabbit inner medullary collecting duct (IMCD) cells, we have examined the effects of kinins on Na+ transport using measurements of oxygen consumption (QO2) and isotopic Na+ uptake. Bradykinin (BK) inhibited IMCD cell QO2 by 24.7 +/- 0.9% without significantly reducing QO2 in cells derived from the outer medullary collecting duct. BK and kallidin half-maximally inhibited QO2 at concentrations in the 10(-12)-10-(-11) M range; beta 1-receptor agonists did not alter QO2, and beta 1-receptor antagonism did not reduce the effect of kinins. These observations indicate that the actions of kinins on IMCD cells are mediated by beta 2-receptors or a distinct subclass. Several observations indicate that kinins reduce QO2 by inhibiting Na+ entry: in the absence of Na+, BK did not reduce QO2; BK inhibition of QO2 was not additive with ouabain, amiloride, atrial natriuretic peptide (ANP), or 8-bromoguanosine 3',5'-cyclic monophosphate and was abolished in the presence of the cation ionophore amphotericin B. Measurements of isotopic Na+ uptake demonstrated that BK reduced the initial rate of Na+ entry by 58%; BK inhibited the amiloride-sensitive component of conductive Na+ uptake. Because ANP inhibits conductive Na+ entry in IMCD cells via stimulation of cGMP accumulation, the effect of BK on cGMP levels was determined. Unlike ANP, BK did not increase cGMP levels, indicating that transport effects of kinins in IMCD are not mediated by cGMP. Thus kinins directly inhibit conductive Na+ entry in IMCD cells at concentrations suggestive of a physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Anti-Malignant Ascites Effect of Total Diterpenoids from Euphorbiae ebracteolatae Radix Is Attributable to Alterations of Aquaporins via Inhibiting PKC Activity in the Kidney

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 942
Author(s):  
Yuanbin Zhang ◽  
Dongfang Liu ◽  
Fan Xue ◽  
Hongli Yu ◽  
Hao Wu ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Antitumor Activity ◽  
Membrane Fraction ◽  
Collecting Duct ◽  
Human Kidney ◽  
Underlying Mechanism ◽  
Malignant Ascites ◽  
Kinase C ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct

This study evaluated the anti-ascites effect of total diterpenoids extracted from Euphorbiae ebracteolatae Radix (TDEE) on malignant ascitic mice and elucidated its underlying mechanism. TDEE was extracted by dichloromethane and subjected to column chromatography. The purity of six diterpenoids isolated from TDEE was determined to be 77.18% by HPLC. TDEE (3 and 0.6 g raw herbs/kg, p.o.) reduced ascites and increased urine output. Meanwhile, analysis of tumor cell viability, cycle and apoptosis indicated that TDEE had no antitumor activity. In addition, the expression levels of aquaporins (AQPs) and the membrane translocation levels of protein kinase C (PKC) α and PKCβ in kidney and cells were measured. TDEE reduced the levels of AQP1–4, and inhibited PKCβ expression in membrane fraction. Four main diterpenoids, except compound 2, reduced AQP1 level in human kidney-2 cells. Compounds 4 and 5 inhibited AQP2–4 expression in murine inner medullary collecting duct cells. The diterpenoid-induced inhibition of AQP1–4 expression was blocked by phorbol-12-myristate-13-acetate (PMA; agonist of PKC). The diterpenoids from TDEE are the main anti-ascites components. The anti-ascites effect of diterpenoids may be associated with alterations in AQPs in the kidneys to promote diuresis. The inhibition of AQP1–4 expression by TDEE is related to the inhibition of PKCβ activation.

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