Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats

Weichert, Wilko; Paliege, Alexander; Provoost, Abraham P.; Bachmann, S.

doi:10.1152/ajprenal.2001.280.4.f706

Cited by 37 publications

(32 citation statements)

References 38 publications

(62 reference statements)

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“…13,19 For immunohistochemistry, the following primary antibodies were used: (1) rabbit monoclonal antibody against an exon 2-encoded NOS1 domain (amino acids 1 to 181 from rat brain; Sigma), (2) rabbit polyclonal antibody against an exon 12 to 21-encoded NOS1 domain (Calbiochem), (3) goat polyclonal antibody against a C-terminal COX-2 peptide (Santa Cruz Biotechnology), and (4) rabbit polyclonal antibody against rat Tamm Horsfall protein (THP; against the whole protein; gift from J. Hoyer, Philadelphia). For detection, Cy3-coupled goat anti-rabbit or donkey anti-goat, and Cy2-coupled mouse anti-rabbit antisera were used (Dianova).…”

Section: Histochemistrymentioning

confidence: 99%

“…Standard incubation procedures were used as described. 13,19 In double-labeling experiments, suitable secondary antibodies coupled to different fluorochromes were applied. …”

mentioning

confidence: 99%

“…12,13 COX-2 expression is increased in high-renin states whether induced by blockade of the renin angiotensin system, 14,15 salt restriction, 9,12,16 unilateral renal artery stenosis, 10,17 or Na,K,2Cl-cotransport inhibition. 18 Neuronal NO synthase (NOS1) is partly co-localized with COX-2-expressing cells of the macula densa and neighboring cTAL cells, 13 and conditions that alter COX-2 expression have earlier been shown to induce analogous changes of NOS1. 13,19 -21 It has therefore been proposed that NO may also be involved in the modulation of the tubulo-vascular responses.…”

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confidence: 99%

“…11 In the rodent renal cortex, the principal site of COX-2 expression is the cortical thick ascending limb (cTAL), including the macula densa region. 12,13 COX-2 expression is increased in high-renin states whether induced by blockade of the renin angiotensin system, 14,15 salt restriction, 9,12,16 unilateral renal artery stenosis, 10,17 or Na,K,2Cl-cotransport inhibition. 18 Neuronal NO synthase (NOS1) is partly co-localized with COX-2-expressing cells of the macula densa and neighboring cTAL cells, 13 and conditions that alter COX-2 expression have earlier been shown to induce analogous changes of NOS1.…”

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Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex

Theilig

Câmpean²,

Paliege³

et al. 2002

Hypertension

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Abstract-In the adult rodent kidney cortex, cyclooxygenase-2 (COX-2), NO synthase (NOS1), and renin synthesis change in parallel on alterations in distal tubular NaCl concentration, and their products in part may mutually determine synthesis and activity of these enzymes. Epithelial NO synthesis has been postulated to exert a stimulatory role on COX-2 expression. Changes in COX-2 and NOS1 may be assessed histochemically by determining changes in the number of positive cells. In rat, macula densa and adjacent cells may co-express COX-2 and NOS1, whereas cell groups of the upstream thick ascending limb (cTAL) express COX-2 alone. We have tested whether the stimulation of COX-2 expression by short-and long-term unilateral renal artery stenosis, low salt, and furosemide treatment depends on co-expression of NOS1. These conditions produced significant respective increases (40% to 351%, PϽ0.05) in the number of COX-2 immunoreactive cells, regardless of whether NOS1 was present or not, suggesting that co-expression of NOS1 is not necessary to produce these changes. Under high-salt conditions, analogous though inverse changes were recorded (Ϫ62% to Ϫ73%, PϽ0.05). In mice with genetic deletion of NOS1, low-and high-salt diets caused similar changes of COX-2 immunoreactivity (106% and Ϫ52%, PϽ0.05) than those seen in wild-type mice (43% and Ϫ78%, PϽ0.05). We conclude that alterations of distal tubular NaCl concentration and presumably NaCl transport induce changes in epithelial COX-2 expression that does not depend on presence of co-expressed NOS1. It therefore seems unlikely that NO is part of a signal transduction chain between tubular chloride sensing and the modulating effects of prostaglandins in tubulo-vascular information transfer. Key Words: nitric oxide synthase Ⅲ macula densa Ⅲ renin Ⅲ juxtaglomerular apparatus Ⅲ prostaglandins T he mammalian kidney is an important site for the synthesis and action of products derived from cyclooxygenase (COX) isoforms (prostaglandin synthase, G2/H2), which catalyze the metabolism of arachidonic acid into biologically active prostanoids. 1 Functional roles for eicosanoid products of COX include the orthograde formation of the nephron during ontogenesis 2 and the modulation of renal salt and water excretion. 3 Recent evidence has highlighted the roles of COX-2 in the tubulo-vascular signaling mechanism of the juxtaglomerular apparatus. 4 -8 The macula densa mechanism for control of renin secretion depends on COX-2-mediated prostaglandin synthesis, because the stimulation of renin activity, secretion, and mRNA expression in response to a decrease in luminal NaCl concentration could be reduced by the administration of COX-2 inhibitors or nonsteroidal antiinflammatory drugs. 8 -10 Additional evidence came from COX-2-deficient mice that failed to increase renal renin content under low-salt conditions. 11 In the rodent renal cortex, the principal site of COX-2 expression is the cortical thick ascending limb (cTAL), including the macula densa region. 12,13 COX-2 expression is increas...

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Section: Histochemistrymentioning

confidence: 99%

“…Standard incubation procedures were used as described. 13,19 In double-labeling experiments, suitable secondary antibodies coupled to different fluorochromes were applied. …”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex

Theilig

Câmpean²,

Paliege³

et al. 2002

Hypertension

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“…Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K ϩ current, and slows the progression of proteinuria and renal injury. kidney; glomerulosclerosis; chronic renal failure; renal hemodynamics THE FAWN-HOODED HYPERTENSIVE (FHH) rat is a genetic model of hypertension (33) that develops proteinuria, glomerulosclerosis (21,30,37,47), and chronic kidney disease (22,(25)(26)(41)(42). We have previously reported that the development of proteinuria and glomerular injury in FHH rats is associated with an impaired autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR), and glomerular capillary pressure (Pgc) (24,40,43,48).…”

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Genetic basis of the impaired renal myogenic response in FHH rats

Burke

Pabbidi

Fan

et al. 2013

American Journal of Physiology-Renal Physiology

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This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K ϩ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K ϩ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K ϩ current, and slows the progression of proteinuria and renal injury. kidney; glomerulosclerosis; chronic renal failure; renal hemodynamics THE FAWN-HOODED HYPERTENSIVE (FHH) rat is a genetic model of hypertension (33) that develops proteinuria, glomerulosclerosis (21,30,37,47), and chronic kidney disease (22,(25)(26)(41)(42). We have previously reported that the development of proteinuria and glomerular injury in FHH rats is associated with an impaired autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR), and glomerular capillary pressure (Pgc) (24,40,43,48). Genetic cosegregation studies identified five quantitative trait loci (QTLs) linked to the development of proteinuria in F2 crosses of FHH and AugustCopenhagen inbred (ACI) rats (4 -5, 36). The rat chromosome (RN) regions are Rf-1 and Rf-2 on RNO1, Rf-3 on RNO3, Rf-4 on RNO14, and Rf-5 on RNO17. The Rf-1 QTL is of particular interest in that it lies within a region that is homologous to an area on human chromosome 10 linked to the development of diabetic nephropathy (19) and end-stage renal disease (18). More recent studies identified a G-to-A mutation in the start codon of Rab38, a gene in the Rf-2 QTL that influences protein trafficking and contributes to the development of proteinuria in FHH rats (32). However, the genes in the Rf-1 region that contribute to the development of proteinuria and renal disease in FHH rats and the mechanisms involved are unknown.We have previously reported that substitution of a 99.4-megabase pair (Mbp) reg...

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Ghrelin modulates intracellular signalling pathways that are critical for podocyte survival

Zein

Abdallah

Daher

et al. 2019

Cell Biochemistry & Function

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Damage to podocytes is a key event in glomerulopathies. While energy dense food can contribute to kidney damage, the role of the orixegenic hormone "ghrelin" in podocyte biology is still unknown. In the present study, we investigated the effect of ghrelin on podocyte survival as well as the signalling pathways mediating ghrelin effect in immortalized cultured rat podocytes. RT-PCR analysis revealed that GHS-R1 is expressed in rat podocytes. Western blot analysis showed that ghrelin upregulated COX-2 protein expression in a time and dose-dependent manner. Additionally, ghrelin activated P38 MAPK, AKT, and ERK1/2 pathways and also induced P38 MAPK phosphorylation in high glucose conditions. Ghrelin induced ROS release and dose dependently reduced podocyte survival. Ghrelin mediated podocyte cell death was partially reversed by pharmacologically inhibiting P38 MAPK or phospholipase C (PLC). Furthermore, PLC inhibitor (U73122) inhibited ghrelin induced P38 MAPK activation. While PI3K inhibitor (LY294002) was without effect on cell survival or P38 MAPK activation, it inhibited ghrelin induced ERK1/2 phosphorylation. Finally, ghrelin induced TAU phosphorylation was reversed by pharmacologic inhibitors of either P38 MAPK or PKA. In conclusion, ghrelin activated harmful molecular pathways in podocytes that can be damaging to the glomerular filtration barrier Significance of the study: Endocrine derangements secondary to obesity are major players in the aetiology of renal injuries. Furthermore, energy dense diet is thought to be the major element in developing obesity. Appetite and increase in energy intake are regulated by complex hormonal pathways which mainly include the orexigenic hormone "ghrelin" in addition to leptin. To date no study have highlighted a significant role for ghrelin in kidney biology, and therefore, it is thought that its endocrine effect is mostly limited to adipose tissue metabolism and appetite regulation. In this study, we first showed that ghrelin receptor is expressed on glomerular podocytes.Also, ghrelin showed negative impact on podocyte survival through modulating signalling pathways such as P38 MAPK and AKT known to play a key role in podocyte health. Moreover, the negative effects of ghrelin on podocytes were further exacerbated in hyperglycemic conditions. Of note, podocytes contribute to the formation and the maintenance of the glomerular filtration barrier and thus are important for Nabil El Zein and Maya S. Abdallah contributed equally to this work.

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Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats

Cited by 37 publications

References 38 publications

Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex

Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex

Genetic basis of the impaired renal myogenic response in FHH rats

Ghrelin modulates intracellular signalling pathways that are critical for podocyte survival

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