scholarly journals Nicotinic Acid Adenine Dinucleotide Phosphate: A New Ca2+ Releasing Agent in Kidney

2001 ◽  
Vol 12 (1) ◽  
pp. 54-60 ◽  
Author(s):  
JINGFEI CHENG ◽  
AHAD N. K. YUSUFI ◽  
MICHAEL A. THOMPSON ◽  
EDUARDO N. CHINI ◽  
JOSEPH P. GRANDE
Keyword(s):  
Renal Function ◽  
Retinoic Acid ◽  
Nicotinic Acid ◽  
Hplc Analysis ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Kidney Cortex ◽  
Cyclic Adp Ribose ◽  
Inositol 1,4,5 Trisphosphate

Abstract. Nicotinic acid adenine dinucleotide phosphate (NAADP), a molecule derived from β-NADP, has been shown to trigger Ca2+ release from intracellular stores of invertebrate eggs and mammalian cell microsomes. NAADP-induced Ca2+ release occurs through a mechanism distinct from that of inositol-1,4,5-trisphosphate— or cyclic ADP-ribose—elicited Ca2+ release. This study investigated whether NAADP can be synthesized in rat kidney. Extracts from glomeruli, mesangial cells, and papilla have high NAADP synthetic capacities. Conversely, synthesis of NAADP in kidney cortex was almost undetectable. Furthermore, 9-cis-retinoic acid significantly up-regulated NAADP synthesis in mesangial cells. Authenticity of NAADP biosynthesis in glomeruli was affirmed by HPLC analysis. NAADP stimulated Ca2+ release from mesangial cell microsomes through a pathway distinct from that of inositol-1,4,5-trisphosphate or cyclic ADP-ribose. NAADP-triggered Ca2+ release may play an important role in regulation of renal function.

Acute lead exposure induces renal haeme oxygenase-1 and decreases urinary Na excretion

2003 ◽  
Vol 22 (5) ◽  
pp. 237-244 ◽  
Author(s):  
Hilda Vargas ◽  
Carlos Castillo ◽  
Francisco Posadas ◽  
Bruno Escalante
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Renal Function ◽  
Lead Exposure ◽  
Lead Acetate ◽  
Single Injection ◽  
Rat Kidney ◽  
Kidney Cortex ◽  
Tin Protoporphyrin ◽  
Pb Exposure

The effects of acute lead exposure on renal function, lipid peroxidation and the expression of haeme oxygenase (HO) in rat kidney were determined. A single injection of lead acetate (50 mg Pb/kg) was given to rats. Changes in renal function, characterized by a significant reduction in the Na excretion was observed six hours after Pb exposure; this effect persisted for 24 hours. TBARS levels increased in kidney cortex 24 hours after Pb administration. In kidney cortex, Pb exposure affected the expression of HO-1, a renal protein associated with oxidative stress. HO-1 mRNA increased 2.3-fold, three hours after Pb administration and remained increased for six, 12 and 24 hours. HO enzymatic activity and HO-1 protein increased six and three hours after Pb administration, respectively, and remained increased at 24 hours. HO inhibition by tin-protoporphyrin, potentiated Pb-induced increase in TBARS and prevented the Pb-induced reduction in Na excretion. Our data suggest that Pb may be acting through the generation of oxidant products and induction of HO.

Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP

1997 ◽  
Vol 77 (4) ◽  
pp. 1133-1164 ◽  
Author(s):  
H. C. Lee
Keyword(s):  
Nitric Oxide ◽  
Nicotinic Acid ◽  
Live Cells ◽  
Release Mechanism ◽  
Major Mechanism ◽  
Signaling Mechanisms ◽  
Signaling Function ◽  
Cyclic Adp Ribose ◽  
Inositol 1,4,5 Trisphosphate ◽  
External Signals

Cells possess various mechanisms for transducing external signals to intracellular responses. The discovery of inositol 1,4,5-trisphosphate (IP3) as a messenger for mobilizing internal Ca2+ stores has centralized Ca2+ mobilization among signaling mechanisms. Results reviewed in this article establish that, in addition to IP3, the internal Ca2+ stores can be mobilized by at least two other molecules, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), via totally independent mechanisms. Cyclic ADP-ribose is a newly discovered cyclic nucleotide derived from NAD, but, unlike adenosine 3',5'-cyclic monophosphate, its main signaling function is modulation of Ca(2+)-induced Ca2+ release, a major mechanism of Ca2+ mobilization in addition to the IP3 pathway. Evidence shows that cADPR may in fact be responsible for mediating the Ca(2+)-mobilizing activity of the gaseous messenger nitric oxide. Cells responsive to cADPR are widespread and include species from plant to mammal, indicating the generality of cADPR as a signaling molecule. In addition to cADPR, NAADP, a metabolite of NADP, can also mobilize Ca2+ stores. The release mechanism and the stores on which NAADP acts are distinct from cADPR and IP3. Nicotinic acid adenine dinucleotide phosphate may play a role in generating Ca2+ oscillations, since liberation of NAADP in live cells by photolyzing its caged analog produces long lasting Ca2+ oscillations. These two new Ca2+ agonists are intimately related, since the same metabolic enzymes can, under appropriate conditions, synthesize either one, suggesting a unified mechanism may regulate both pathways. Elucidation of these two new Ca2+ mobilization pathways is likely to have an important impact on our understanding of cellular signaling mechanisms.

Myo-inositol and D-glucose transport in rat glomerular and cultured mesangial cells

1991 ◽  
Vol 260 (1) ◽  
pp. F138-F144 ◽  
Author(s):  
C. I. Whiteside ◽  
J. C. Thompson ◽  
J. Ohayon
Keyword(s):  
Glucose Transport ◽  
Mesangial Cells ◽  
Intact Cell ◽  
Rat Kidney ◽  
Kidney Cortex ◽  
Cellular Transport ◽  
Sprague Dawley ◽  
Rat Kidney Cortex ◽  
Disease States ◽  
Glomerular Epithelial Cells

Myo-inositol (MI) is the precursor of membrane-bound phosphoinositides important for transmembrane signaling. This study examines whether freshly isolated whole glomeruli can be used to characterize intact cell transport kinetics for MI and D-glucose. Transport properties of cultured mesangial cells are compared. Glomeruli greater than 95% tubule free were isolated from Sprague-Dawley rat kidney cortex by means of selective sieving. Scanning electron microscopy revealed substantial damage of glomerular epithelial cells, whereas endothelial and mesangial cells remained intact. Specific [3H]MI uptake (7-180 min, 37 degrees C) was observed in presence of 5.5 mM D-glucose when L-[14C]glucose was used as a marker of nonspecific uptake. With ouabain (3 mM), or when Na was replaced with N-methyl-D-glucamine, choline, or Li, specific MI uptake was reduced by 95%. A single high-affinity, Na-dependent MI transport site on glomerular cells with Km of 16.5 +/- 1.4 (SE) microM and Vmax of 947 +/- 56 (SE) fmol.mg protein-1.min-1 was observed for 0.75-100 microM MI. D-glucose competitively inhibited MI transport. Specific D-[3H]-glucose transport was Na independent. Phlorizin inhibition of D-glucose and MI uptake was in keeping with Na-independent D-glucose transport. Km and Vmax for MI uptake in cultured mesangial cells were 42.7 +/- 7.1 microM and 1,474 +/- 192 fmol.mg protein-1.min-1, respectively. We conclude that freshly isolated glomeruli can be used to study cellular transport function that may be modified in disease states.

scholarly journals TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression

2020 ◽  
Vol 295 (42) ◽  
pp. 14262-14278
Author(s):  
Soumya Maity ◽  
Falguni Das ◽  
Balakuntalam S. Kasinath ◽  
Nandini Ghosh-Choudhury ◽  
Goutam Ghosh Choudhury
Keyword(s):  
Growth Factor ◽  
Matrix Protein ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Kidney Cortex ◽  
Glomerular Mesangial Cells ◽  
Cell Hypertrophy ◽  
Tgfβ Receptor ◽  
Mtorc1 Activation ◽  
Noncanonical Signaling

Interaction of transforming growth factor-β (TGFβ)-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of the TGFβ receptor involved in the noncanonical signaling is unknown. Here, we show that TGFβ increased the catalytic loop phosphorylation of platelet-derived growth factor receptor β (PDGFRβ), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFβ increased phosphorylation of the PI 3-kinase–interacting Tyr-751 residue of PDGFRβ, thus activating Akt. Inhibition of PDGFRβ using a pharmacological inhibitor and siRNAs blocked TGFβ-stimulated phosphorylation of proline-rich Akt substrate of 40 kDa (PRAS40), an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active myristoylated Akt reversed the siPDGFRβ-mediated inhibition of mTORC1 activity; however, co-expression of the phospho-deficient mutant of PRAS40 inhibited the effect of myristoylated Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRβ in mesangial cells. Additionally, we demonstrate that PDGFRβ-initiated phosphorylation of PRAS40 is required for TGFβ-induced mesangial cell hypertrophy and fibronectin and collagen I (α2) production. Increased activating phosphorylation of PDGFRβ is also associated with enhanced TGFβ expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rats, respectively. Thus, pursuing TGFβ noncanonical signaling, we identified how TGFβ receptor I achieves mTORC1 activation through PDGFRβ-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRβ in TGFβ-driven renal fibrosis.

scholarly journals Morphological Insights into the Origin of Glomerular Endothelial and Mesangial Cells and Their Precursors

2003 ◽  
Vol 51 (2) ◽  
pp. 141-150 ◽  
Author(s):  
Jill M. Ricono ◽  
Yi-Chun Xu ◽  
Mazen Arar ◽  
Dong-chan Jin ◽  
Jeffrey L. Barnes ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Kidney Development ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Temporal Distribution ◽  
Metanephric Mesenchyme ◽  
Early Stages ◽  
Glomerular Capillary ◽  
In Cells

Glomerular endothelial and mesangial cells may originate from the metanephric mesenchyme. We used the MAb Thy1.1, a mesangial cell marker in the adult rat kidney, and rat endothelial cell markers MAb RECA-1, MAb PECAM-1 (CD31), and MAb Flk-1 as potential markers to characterize the spatial and temporal distribution of mesangial and endothelial cell precursors during nephrogenesis in the rat. At early stages of glomerulogenesis, RECA-1- and Thy1.1-positive cells were detected in the metanephric blastema at 14 days post conception (dpc) embryos and 15 dpc, respectively, with Thy1.1 expression in cells surrounding the ureteric bud. At 17 and 18 dpc, both RECA-1- and Thy1.1-positive cells were found in the cleft of the S-shaped bodies and in the capillary loops of maturing glomeruli. Double staining for BrdU, a marker of proliferation, and for RECA-1 or BrdU and Thy1.1 also localize in the cleft of S-shaped bodies and in glomerular capillary loops at later stages of development. PDGFRβ co-localizes in cells expressing endothelial or mesangial markers. The data suggest that endothelial and mesangial cell precursors share common markers during the course of glomerulogenesis and that full differentiation of these cells occurs at late stages of glomerular maturation. Thy1.1- and RECA-1-positive cells may be derived from the metanephric blastemal cells at early stages of kidney development. A sub-population of these Thy1.1- or RECA-1-positive cells may be precursors that can migrate into the cleft of comma and S-shaped bodies and proliferate in situ to form glomerular capillary tufts.

scholarly journals Expression of a Novel PDGF Isoform, PDGF-C, in Normal and Diseased Rat Kidney

2002 ◽  
Vol 13 (4) ◽  
pp. 910-917 ◽  
Author(s):  
Frank Eitner ◽  
Tammo Ostendorf ◽  
Claudia Van Roeyen ◽  
Masashi Kitahara ◽  
Xuri Li ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Renal Scarring ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Factor C

ABSTRACT. Platelet-derived growth factor-C (PDGF-C) is a new member of the PDGF family. Its expression in normal and diseased kidney is unknown. Rabbit antisera were generated against human full-length, core domain, and mouse PDGF-C, and their specificity was confirmed by Western blot analyses. Renal PDGF-C expression was analyzed by immunohistochemistry in normal rats (n = 8), mesangioproliferative anti-Thy 1.1 nephritis (n = 4 each at days 1, 4, 6, and 85), passive Heymann nephritis (PHN, n = 4), puromycin nephrosis (PAN, n = 2), Milan normotensive rats (MN, n = 2), and obese Zucker rats (n = 3). PDGF-C expression was also studied in anti-Thy 1.1 rats treated with PDGF-B aptamer antagonists (n = 5) or irrelevant control aptamers (n = 5). PDGF-C was constitutively expressed in arterial smooth muscle cells and collecting duct epithelial cells. Mesangial PDGF-C was markedly upregulated in anti-Thy 1.1 nephritis in parallel with the peak mesangial cell proliferation. Furthermore, PDGF-CC acted as a potent growth factor for mesangial cells in vitro. Inhibition of PDGF-B via specific aptamers reduced the injury in anti-Thy 1.1 nephritis but did not affect the glomerular PDGF-C overexpression or the mitogenicity of PDGF-CC in vitro. In PHN, PAN, and obese Zucker rats, glomeruli remained negative for PDGF-C despite severe glomerular injury. PDGF-C localized to podocytes at sites of focal and segmental sclerosis in MN. Interstitial PDGF-C expression was increased at sites of fibrosing injury in obese Zucker rats. The use of the different antisera resulted in virtually identical findings. It is concluded that PDGF-C is a novel mesangial cell mitogen that is constitutively expressed in the kidney and specifically upregulated in mesangial, visceral epithelial, and interstitial cells after predominant injury to these cells. PDGF-C may therefore be involved in the pathogenesis of renal scarring.

Alpha 1-VIII collagen is expressed in the rat glomerulus and in resident glomerular cells

1993 ◽  
Vol 264 (6) ◽  
pp. F1003-F1010 ◽  
Author(s):  
N. D. Rosenblum ◽  
D. M. Briscoe ◽  
M. J. Karnovsky ◽  
B. R. Olsen
Keyword(s):  
Renal Cortex ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Current Knowledge ◽  
Rat Kidney ◽  
Three Dimensional ◽  
Short Chain ◽  
Type Viii ◽  
Normal Rat ◽  
The Media

Current knowledge regarding the molecular composition of extracellular matrices in the glomerulus does not explain how these components interact to form stable three-dimensional structures. The recent recognition that short-chain collagens such as type VIII collagen function as molecular bridges in some nonrenal tissues has raised the possibility that such molecules may serve a similar function in the glomerulus. We have recently shown that cultured rat mesangial cells synthesize and secrete several short-chain collagenous proteins, one of which has properties similar to alpha 1-VIII collagen. In the present study we have isolated a rat mesangial cell alpha 1-VIII collagen cDNA clone, the sequence of which is 81% homologous to mouse alpha 1-VIII collagen. We used this cDNA to determine that alpha 1-VIII collagen mRNA is expressed in rat renal cortex and in cultured glomerular mesangial, epithelial, and endothelial cells. Additionally, we demonstrated that alpha 1-VIII collagen is secreted by cultured mesangial cells as an 80-kDa translation product. By immunocytochemistry, alpha 1-VIII collagen localized to the media of large intrarenal arteries and to the capillary loops and the mesangium of normal rat kidney. These results indicate that type VIII collagen is a normal constituent of the rat glomerulus as well as large intrarenal arteries. We speculate that type VIII collagen may function in part to determine the three-dimensional organization of the subendothelial and mesangial matrices.

scholarly journals Immunolocalization of Protein Kinase C Isoenzymes α, βI and βII in Rat Kidney

1999 ◽  
Vol 10 (9) ◽  
pp. 1861-1873
Author(s):  
IMKE L. PFAFF ◽  
HANS-JOACHIM WAGNER ◽  
VOLKER VALLON
Keyword(s):  
Renal Function ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Mesangial Cells ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Loop Of Henle ◽  
Mhc Ii ◽  
Luminal Membrane ◽  
Kinase C

Abstract. Protein kinase C (PKC) significantly contributes to the control of renal function, but little is known about the renal function or localization of PKC isoenzymes. Therefore, the localization of PKC isoenzymes α, βI, and βII was studied in rat kidney. Immunoblot analysis identified immunoreactive bands corresponding to PKC α, βI, and βII in total cell extracts of both renal cortex and medulla. Immunohistochemistry using confocal laser scanning microscopy revealed immunostaining for PKC α within the glomerulus including podocytes and mesangial cells. PKC βI was detected in mesangial cells, whereas anti-PKC βII labeled neither podocytes nor mesangial cells. PKC βII, however, was detected in cells within the mesangial area, which expressed MHC II, a marker for antigen-presenting cells. None of the three isoforms was detected in glomerular endothelial cells. A prominent immunostaining with anti-PKC α and βI was localized to the brush border of S2 and S3 segments of proximal tubule, whereas S1 segments were not stained. Along the loop of Henle, both PKC α and PKC βI were found in the luminal membrane of cortical and medullary thick ascending limb. In addition, anti-PKC βI labeled the luminal membrane of thin limbs. In the cortical collecting duct (CCD), immunofluorescence for PKC α was observed at the apical membrane of both peanut agglutinin (PNA)-negative cells and part of PNA-positive cells, whereas in the medullary collecting duct (MCD), PKC α was detected at the basolateral membrane. In comparison, PKC βI was localized at the luminal membrane of PNA-positive cells only in CCD and at the luminal membrane of MCD. Unlike PKC α or βI, there was (1) no detectable immunostaining with anti-PKC βII in the proximal tubule, the loop of Henle, or the CCD and (2) a distinct staining for PKC βII of interstitial cells in cortex and medulla (including MHC II-positive dendritic cells). Furthermore, PKC βII was detected in the luminal membrane of MCD. In summary, a distinct and differential expression pattern for PKC α, βI, and βII was shown in rat kidney, which may contribute to a better understanding of the specific role of these isoenzymes in the control of renal function.

Nicotinic acid–adenine dinucleotide phosphate (NAADP) elicits specific microsomal Ca2+ release from mammalian cells

2001 ◽  
Vol 353 (3) ◽  
pp. 531-536 ◽  
Author(s):  
Ahad N.-K. YUSUFI ◽  
Jingfei CHENG ◽  
Michael A. THOMPSON ◽  
Eduardo N. CHINI ◽  
Joseph P. GRANDE
Keyword(s):  
Nicotinic Acid ◽  
Intracellular Calcium ◽  
Sea Urchin ◽  
Mammalian Cells ◽  
Calcium Release ◽  
Cultured Cells ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Leukaemia Cell Line ◽  
Mammalian Tissues

Nicotinic acid–adenine dinucleotide phosphate (NAADP), a molecule derived from β-NADP, has been shown to promote intracellular calcium release in sea urchin eggs. However, there is little information regarding the role of NAADP in the regulation of intracellular calcium fluxes in mammalian cells. We found recently that several mammalian tissues have a high capacity for NAADP synthesis, as assessed by sea urchin egg bioassay. To determine the functional significance of NAADP production by mammalian tissues, we sought to determine whether NAADP is capable of inducing calcium release from microsomes prepared from cultured cells. We found that NAADP, but not β-NADP, activates a specific microsomal calcium release system in mesangial cells isolated from rat kidney; NAADP was without effect in renal tubular epithelial cells. NAADP-induced calcium release is not affected by inhibitors of the inositol 1,4,5-trisphosphate or ryanodine channels. However, NAADP-elicited calcium release was inhibited by L-type calcium channel blockers and by alkaline phosphatase treatment of NAADP. NAADP also promotes specific microsomal calcium release in rat vascular smooth muscle cells, cardiac myocytes, fibroblasts and a human leukaemia cell line, indicating that the capacity for NAADP-induced calcium release is widespread in mammalian cells. We propose that NAADP may be an important regulator of intracellular calcium in many mammalian tissues.

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