Eicosanoids and tumor necrosis factor-alpha in the kidney

Ferreri, Nicholas R.; Hao, Shoujin; Pedraza, Paulina L.; Escalante, Bruno; Vio, Carlos P.

doi:10.1016/j.prostaglandins.2011.11.002

Cited by 15 publications

(7 citation statements)

References 99 publications

(99 reference statements)

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“…These data are consistent with a recent study showing that salt loading increased TNF-α production by the kidney, 23 and more specifically the TAL, 22 an effect that is greatly accentuated in Umod KO mice. The elevated levels of urinary TNF-α observed in KO mice suggests that cell-surface UMOD in the WT animals sequesters TNF-α, limiting the amount of cytokine that is excreted.…”

Section: Discussionsupporting

confidence: 93%

Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension

et al. 2014

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A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin ( UMOD ) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P <0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P <0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice ( P <0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na + excretion and further Na + loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice ( P <0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression ( P <0.001) with a concurrent rise in the levels of UMOD mRNA ( P <0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.

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Section: Discussionsupporting

confidence: 93%

Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension

et al. 2014

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“…COX2 is over-expressed in about 85% of colorectal adenocarcinomas and it is responsible for the synthesis of prostaglandins that play a major role during the inflammatory response, hence in colitis and in colitis-associated colorectal cancer [40,56]. In our model, the CaSR stimulated COX2 expression, as it does also in kidney cells [57] and in inflamed lung [49]. PDL-1 is an immune checkpoint protein and it is over-expressed by cancer cells to escape immune surveillance, inhibiting lymphocyte activation [41].…”

Section: Discussionmentioning

confidence: 73%

Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

Iamartino

Elajnaf

Gall

et al. 2020

Preprint

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The calcium-sensing receptor (CaSR) is a ubiquitously expressed multifunctional G protein-coupled receptor. Several studies reported that the CaSR plays an anti-inflammatory and anti-tumorigenic role in the intestine, and that it is down-regulated during colorectal carcinogenesis. We hypothesized that intestine-specific positive allosteric CaSR modulators (type II calcimimetics) could be used for the treatment of intestinal pathologies. Therefore, the aim of this study was to determine the effect of pharmacological stimulation of CaSR on gene expression in vitro and on tumor growth in vivo. We stably transduced two colon cancer cell lines (HT29 and Caco2) with lentiviral vectors containing either the CaSR fused to GFP or GFP only. Using RNA sequencing, RT-qPCR experiments and ELISA, we determined that CaSR over-expression itself had generally little effect on gene expression in these cells. However, treatment with 1μM of the calcimimetic NPS R-568 increased the expression of pro-inflammatory factors such as IL-23α and IL-8 and reduced the transcription of various differentiation markers in the cells over-expressing the CaSR. In vivo, neither the presence of the CaSR nor p.o. treatment of the animals with the calcimimetic cinacalcet affected tumor growth, tumor cell proliferation or tumor vascularization of murine HT29 xenografts. In summary, CaSR stimulation in CaSR over-expressing cells enhanced the expression of inflammatory markers in vitro, but was not able to repress colorectal cancer tumorigenicity in vivo. These findings suggest potential pro-inflammatory effects of the CaSR and type II calcimimetics in the intestine.

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“…The mechanism by which L-tryptophan, L-valine and glutamyl dipeptides mediate the CaSR-dependent inhibition of pro-inflammatory cytokine secretion in colonocytes appears to require β-arrestin 2[ 20 , 21 ]. Moreover, in the thick ascending limb of the kidneys, the CaSR has been shown to induce TNF-α-dependent cyclooxygenase 2 expression and prostaglandin E 2 synthesis via a G i -dependent mechanism[ 40 ]. However, the exact mechanism by which the CaSR regulates inflammation is still unclear and needs further investigation.…”

Section: Role Of the Casr In Inflammationmentioning

confidence: 99%

Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives

Iamartino¹,

Elajnaf²,

Kállay³

et al. 2018

WJG

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The extracellular calcium-sensing receptor (CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the CaSR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitis-associated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.

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Eicosanoids and tumor necrosis factor-alpha in the kidney

Cited by 15 publications

References 99 publications

Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension

Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension

Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives

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