scholarly journals Role of Substance P in Renal Injury During DOCA-Salt Hypertension

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5972-5979 ◽  
Author(s):  
Youping Wang ◽  
Donna H. Wang
Keyword(s):  
Substance P ◽  
Renal Injury ◽  
Tissue Injury ◽  
Periodic Acid ◽  
Sensory Nerves ◽  
Macrophage Infiltration ◽  
Tubulointerstitial Injury ◽  
Salt Treatment ◽  
Albumin Excretion ◽  
Salt Hypertension

Abstract Substance P (SP), a neurokinin-1 receptor (NK-1R) agonist, is mainly produced and stored in primary sensory nerves and, upon its release, participates in cardiovascular and renal functional regulation. This study tests the hypothesis that activation of the NK-1Rs by SP occurs during hypertension induced by deoxycorticosterone (DOCA)-salt treatment, which contributes to renal injury in this model. C57BL/6 mice were subjected to uninephrectomy and DOCA-salt treatment in the presence or absence of administration of selective NK-1 antagonists, L-733,060 (20 mg/kg·d, ip) or RP-67580 (8 mg/kg·d, ip). Five weeks after the treatment, mean arterial pressure determined by the telemetry system increased in DOCA-salt mice but without difference between NK-1R antagonist-treated or NK-1R antagonist-untreated DOCA-salt groups. Plasma SP levels were increased in DOCA-salt compared with control mice (P < 0.05). Renal hypertrophy and increased urinary 8-isoprostane and albumin excretion were observed in DOCA-salt compared with control mice (P < 0.05). Periodic acid-Schiff and Masson's trichrome staining showed more severe glomerulosclerosis and tubulointerstitial injury in the renal cortex in DOCA-salt compared with control mice, respectively (P < 0.05). Hydroxyproline assay and F4/80-staining showed that renal collagen levels and interstitial monocyte/macrophage infiltration were greater in DOCA-salt compared with control mice, respectively (P < 0.05). Blockade of the NK-1R with L-733,060 or RP-67580 in DOCA-salt mice suppressed increments in urinary 8-isoprostane and albumin excretion, interstitial monocyte/macrophage infiltration, and glomerulosclerosis and tubulointerstitial injury and fibrosis (P < 0.05). Thus, our data show that blockade of the NK-1Rs alleviates renal functional and tissue injury in the absence of alteration in blood pressure in DOCA-salt-hypertensive mice. The results suggest that elevated SP levels during DOCA-salt hypertension play a significant role contributing to renal damage possibly via enhancing oxidative stress and macrophage infiltration of the kidney.

scholarly journals Aggravated renal inflammatory responses in TRPV1 gene knockout mice subjected to DOCA-salt hypertension

2009 ◽  
Vol 297 (6) ◽  
pp. F1550-F1559 ◽  
Author(s):  
Youping Wang ◽  
Donna H. Wang
Keyword(s):  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Gene Knockout ◽  
Periodic Acid ◽  
Immunosuppressive Drug ◽  
Transient Receptor Potential Vanilloid ◽  
Tubulointerstitial Injury ◽  
Salt Treatment ◽  
Periodic Acid Schiff ◽  
Salt Hypertension

To test the hypothesis that deletion of the transient receptor potential vanilloid type 1 (TRPV1) channel exaggerates hypertension-induced renal inflammatory response, wild-type (WT) or TRPV1-null mutant (TRPV1−/−) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 wk. Mean arterial pressure (MAP) determined by radiotelemetry increased in DOCA-salt-treated WT or TRPV1−/− mice, whereas there was no difference in MAP between two strains at the baseline or after DOCA-salt treatment. DOCA-salt treatment increased urinary excretion of albumin and 8-isoprostane in both WT and TRPV1−/− mice, and the increases were greater in magnitude in the latter strain. Periodic acid-Schiff and Mason's trichrome staining showed that kidneys of DOCA-salt-treated TRPV1−/− mice exhibited more severe glomerulosclerosis and tubulointerstitial injury compared with DOCA-salt-treated WT mice. NF-κB assay showed that DOCA-salt treatment increased renal activated NF-κB concentrations in TRPV1−/− mice compared with WT mice. Immunostaining and ELISA assay revealed that DOCA-salt-treated TRPV1−/− mice had enhanced renal infiltration of monocyte/macrophage and lymphocyte, as well as increased renal levels of proinflammatory cytokine (TNF-α, IL-6) and chemokine (MCP-1) compared with DOCA-salt-treated WT mice. Renal ICAM-1 but not VCAM-1 expression was also greater in DOCA-salt-treated TRPV1−/− than WT mice. Dexamethasone (DEXA), an immunosuppressive drug, conveyed a renoprotective effect that was greater in DOCA-salt-treated TRPV1−/− compared with WT mice. These data show that renal inflammation is exacerbated in DOCA-salt hypertension when TRPV1 gene is deleted and that the deterioration is ameliorated by DEXA treatment, indicating that TRPV1 may act as a potential regulator of the inflammatory process to lessen renal injury in DOCA-salt hypertension.

P2X7 deficiency attenuates hypertension and renal injury in deoxycorticosterone acetate-salt hypertension

2012 ◽  
Vol 303 (8) ◽  
pp. F1207-F1215 ◽  
Author(s):  
Xu Ji ◽  
Yukiko Naito ◽  
Huachun Weng ◽  
Kosuke Endo ◽  
Xiao Ma ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Inflammatory Diseases ◽  
Receptor Expression ◽  
Salt Treatment ◽  
Deoxycorticosterone Acetate ◽  
Salt Diet ◽  
Salt Hypertension ◽  
Mrna And Protein Expression

The P2X7 receptor is a ligand-gated ion channel, and genetic variations in the P2X7 gene significantly affect blood pressure. P2X7 receptor expression is associated with renal injury and inflammatory diseases. Uninephrectomized wild-type (WT) and P2X7-deficient (P2X7 KO) mice were subcutaneously implanted with deoxycorticosterone acetate (DOCA) pellets and fed an 8% salt diet for 18 days. Their blood pressure was assessed by a telemetry system. The mice were placed in metabolic cages, and urine was collected for 24 h to assess renal function. After 18 days of DOCA-salt treatment, P2X7 mRNA and protein expression increased in WT mice. Blood pressure in P2X7 KO mice was less than that of WT mice (mean systolic blood pressure 133 ± 3 vs. 150 ± 2 mmHg). On day 18, urinary albumin excretion was lower in P2X7 KO mice than in WT mice (0.11 ± 0.07 vs. 0.28 ± 0.07 mg/day). Creatinine clearance was higher in P2X7 KO mice than in WT mice (551.53 ± 65.23 vs. 390.85 ± 32.81 μl·min−1·g renal weight−1). Moreover, renal interstitial fibrosis and infiltration of immune cells (macrophages, T cells, B cells, and leukocytes) were markedly attenuated in P2X7 KO mice compared with WT mice. The levels of IL-1β, released by macrophages, in P2X7 KO mice had decreased dramatically compared with that in WT mice. These results strongly suggest that the P2X7 receptor plays a key role in the development of hypertension and renal disease via increased inflammation, indicating its potential as a novel therapeutic target.

Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension

1999 ◽  
Vol 276 (3) ◽  
pp. R766-R775 ◽  
Author(s):  
A. O. Oyekan ◽  
K. McAward ◽  
J. Conetta ◽  
L. Rosenfeld ◽  
John C. McGiff
Keyword(s):  
Tissue Injury ◽  
Left Ventricular ◽  
Arachidonic Acid Metabolism ◽  
Salt Treatment ◽  
Fourfold Increase ◽  
Protein Excretion ◽  
Salt Hypertension ◽  
Arachidonate Metabolites ◽  
Cytochrome P 450 ◽  
Cyp450 Enzyme

Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 ± 6 mmHg by day 21 from control levels of 150 ± 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg ⋅ kg−1 ⋅ 24 h−1). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 ± 6.9 mg/24 h on day 21 from 9.0 ± 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 ± 17 to 277 ± 104 pg ⋅ 100 g body wt−1 ⋅ 24 h−1 associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 ± 1.1 to 12.2 ± 1.9 ng ⋅ 100 g body wt−1 ⋅ 24 h−1( days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [3H]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [3H]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SBP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.

Mast cell-nerve fiber interaction: Ultrastructural studies

1990 ◽  
Vol 48 (3) ◽  
pp. 428-429
Author(s):  
E.Y. Chi ◽  
M.L. Su ◽  
Y.T. Tien ◽  
W.R. Henderson
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Substance P ◽  
Nerve Fiber ◽  
Sensory Nerves ◽  
Ultrastructural Studies ◽  
Morphological Studies ◽  
Granulocyte Infiltration ◽  
Intracutaneous Injection ◽  
Recent Attention

Recent attention has been directed to the interaction of the nerve and immune systems. The neuropeptide substance P, a tachykinnin which is a neurotransmitter in the central and peripheral nervous systems produces tissue swelling, augemntation of intersitial fibrin deposition and leukocyte infiltration after intracutaneous injection. There is a direct correlation reported between the extent of mast cell degranulation at the sites of injection and the tissue swelling or granulocyte infiltration. It has previously been demonstrated that antidromic electrical stimulation of sensory nerves induces degranulation of cutaneous mast cells, cutaneous vasodilation and augmented vascular permeability. Morphological studies have documented a close anatiomical association between mast cells and nonmyelinated nerves, that contain substance P and other neuropeptides. However, the presence of mast cells within nerve fasicles has not been previously examined ultrastructurally. In this study, we examined ultrastructurally the distribution of mast cells in the nerve fiber bundles located in the muscular connective tissue of rat tongues (n=20).

scholarly journals The pathological features of leukemic cells infiltrating the renal interstitium in chronic lymphocytic leukemia/small lymphocytic lymphoma from a large single Chinese center

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Hui Wang ◽  
Xiaojuan Yu ◽  
Xu Zhang ◽  
Suxia Wang ◽  
Minghui Zhao
Keyword(s):  
Electron Microscopy ◽  
Chronic Lymphocytic Leukemia ◽  
Renal Injury ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Cell Infiltration ◽  
Small Lymphocytic Lymphoma ◽  
Tubulointerstitial Injury ◽  
Renal Interstitium ◽  
Monoclonal Immunoglobulins

Abstract Background Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare in Asians, and patients with CLL/SLL seldomly undergo kidney biopsy. The histopathological features and clinical relevance of tubulointerstitial injury in CLL/SLL have not been extensively characterized. Hence, we attempted to describe the clinical characteristics, renal pathology and clinical outcome of a well-characterized population of CLL/SLL patients with CLL cell infiltration in the renal interstitium from a large single center in China. Methods Between January 1st, 2010 and September 31st, 2020, 31946renal biopsies were performed at Peking University First Hospital, and 10 CLL/SLL patients with CLL cell infiltration in the renal interstitium were included. Complete clinical data were collected from these 10 patients, and renal specimens were examined by routine light microscopy, immunofluorescence and electron microscopy. Results The extent of the infiltrating CLL cells in patients with CLL/SLL varied among different patients and ranged from 10 to 90% of kidney parenchyma. Six (60%) of 10 patients presented with an extent of infiltrating CLL cells ≥50%. Interestingly, we found that three patients (3/10, 30%) expressed monoclonal immunoglobulins in the infiltrating CLL cells, and special cytoplasmic crystalline structures were found in two of the three patients by electron microscopy for the first time. Severe renal insufficiency (Scr ≥200 μmol/L) was associated with ≥50% interstitial infiltration of CLL cells in the renal interstitium. Conclusions The current study confirmed that CLL cells infiltrating the renal interstitium can directly secrete monoclonal immunoglobulins, indicating that the interstitial infiltrating CLL cells possibly cause renal injury directly by secreting monoclonal immunoglobulins in situ. This finding may prove a new clue to elucidate the pathogenetic mechanism of renal injury involved with CLL/SLL.

scholarly journals 4-Hydroxychalcone Attenuates Hyperaldosteronism, Inflammation, and Renal Injury in Cryptochrome-Null Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Qi Qu ◽  
Bingguang Dai ◽  
Bo Yang ◽  
Xuelian Li ◽  
Yimin Liu ◽  
...  
Keyword(s):  
Resistant Hypertension ◽  
Renal Injury ◽  
Systolic Pressure ◽  
Kidney Injury ◽  
High Plasma ◽  
Salt Treatment ◽  
Injury Treatment ◽  
The Impact ◽  
Preventive Effects ◽  
Light Chain Enhancer

In the present study, we aimed to investigate the preventive effects of 4-hydroxychalcone (4HCH) on resistant hypertension. We used cryptochrome-null mice, which characteristically show high plasma aldosterone levels, inflammation, and renal injury. The cryptochrome-null mice received high-salt treatment and were treated orally with 4HCH 10 mg/kg, 4HCH 20 mg/kg, and 4HCH 40 mg/kg, respectively. The salt administration in cryptochrome-null mice is able to induce an increase in systolic pressure which is associated with hyperaldosteronism, inflammation, and kidney injury. Treatment with 40 mg/kg 4HCH reduced systolic hypertension, serum IL-1β, and TNF-αlevels and suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and renal injury. The impact of 4HCH on the hyperaldosteronism, inflammation, and kidney injury provides new insights for future development of therapeutic strategies in resistant hypertension.

scholarly journals Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats

2013 ◽  
Vol 304 (8) ◽  
pp. R675-R682 ◽  
Author(s):  
Jan Mulder ◽  
Tomas Hökfelt ◽  
Mark M. Knuepfer ◽  
Ulla C. Kopp
Keyword(s):  
Substance P ◽  
Optical Density ◽  
Renal Denervation ◽  
Time Course ◽  
Sympathetic Nerves ◽  
Sensory Nerves ◽  
Sensory Innervation ◽  
Multiple Time ◽  
Sensory Reinnervation ◽  
Renal Sympathetic

Efferent renal sympathetic nerves reinnervate the kidney after renal denervation in animals and humans. Therefore, the long-term reduction in arterial pressure following renal denervation in drug-resistant hypertensive patients has been attributed to lack of afferent renal sensory reinnervation. However, afferent sensory reinnervation of any organ, including the kidney, is an understudied question. Therefore, we analyzed the time course of sympathetic and sensory reinnervation at multiple time points (1, 4, and 5 days and 1, 2, 3, 4, 6, 9, and 12 wk) after renal denervation in normal Sprague-Dawley rats. Sympathetic and sensory innervation in the innervated and contralateral denervated kidney was determined as optical density (ImageJ) of the sympathetic and sensory nerves identified by immunohistochemistry using antibodies against markers for sympathetic nerves [neuropeptide Y (NPY) and tyrosine hydroxylase (TH)] and sensory nerves [substance P and calcitonin gene-related peptide (CGRP)]. In denervated kidneys, the optical density of NPY-immunoreactive (ir) fibers in the renal cortex and substance P-ir fibers in the pelvic wall was 6, 39, and 100% and 8, 47, and 100%, respectively, of that in the contralateral innervated kidney at 4 days, 4 wk, and 12 wk after denervation. Linear regression analysis of the optical density of the ratio of the denervated/innervated kidney versus time yielded similar intercept and slope values for NPY-ir, TH-ir, substance P-ir, and CGRP-ir fibers (all R2 > 0.76). In conclusion, in normotensive rats, reinnervation of the renal sensory nerves occurs over the same time course as reinnervation of the renal sympathetic nerves, both being complete at 9 to 12 wk following renal denervation.

Abstract 103: ACE2 Overexpression Prevents DOCA-Salt Hypertension by Modulating Oxidative Stress and Nitric Oxide in the Central Nervous System

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Srinivas Sriramula ◽  
Huijing Xia ◽  
Eric Lazartigues
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Central Nervous System ◽  
Nervous System ◽  
Nadph Oxidase ◽  
Salt Treatment ◽  
Salt Hypertension ◽  
The Central Nervous System ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Elevated reactive oxygen species (ROS) in the central nervous system (CNS) through NADPH oxidase and diminished Nitric oxide (NO) levels are involved in the pathogenesis of hypertension. We previously reported that central Angiotensin Converting Enzyme 2 (ACE2) overexpression prevents the development of hypertension induced by DOCA-salt in a transgenic mouse model (syn-hACE2; SA) with human ACE2 targeted selectively to neurons in the CNS. While baseline blood pressure (BP; telemetry) was not different among genotypes, DOCA-salt treatment (1mg/g body wt DOCA, 1% saline in drinking water for 3 weeks) resulted in significantly lower BP level in SA mice (122 ±3 mmHg, n=12) compared to non-transgenic (NT) littermates (138 ±3 mmHg, n=8). To elucidate the mechanisms involved in this response, we investigated the paraventricular nucleus (PVN) expression of Nox-2 (catalytic subunit of NADPH oxidase), 3-nitrotyrosine, and endothelial nitric oxide synthase (eNOS) and anti-oxidant enzymes superoxide dismutase (SOD) and catalase in the hypothalamus. DOCA-salt treatment resulted in decreased catalase (95.2 ±5.6 vs. 113.8 ±17.6 mmol/min/ml, p<0.05) and SOD (4.1 ±0.4 vs. 5.9 ±0.2 U/ml, p<0.01) activities in hypothalamic homogenates of NT mice, which was prevented by ACE2 overexpression (141.8 ±9.9 vs. 142.1 ±9.2 mmol/min/ml and 5.9 ±0.3 vs. 7.9 ±0.2 U/ml, respectively). NT mice treated with DOCA-salt showed increased oxidative stress as indicated by increased expression of Nox-2 (61 ±5 % increase, n=9, p<0.001 vs. NT) and 3-nitrotyrosine (89 ±32 % increase, n=9, p<0.01 vs. NT) in the PVN which was attenuated in SA mice. Furthermore, DOCA-salt hypertension resulted in decreased phosphorylation of eNOS-ser1177 in the PVN (33 ±5 % decrease, n=9, p<0.05 vs NT) and this decrease was prevented by ACE2 overexpression. Taken together, these data provide evidence that brain ACE2 regulates the balance between NO and ROS levels, thereby preventing the development of DOCA-salt hypertension.

Endothelium, vasopressin receptors, and resistance to DOCA-salt hypertension

1993 ◽  
Vol 265 (1) ◽  
pp. H15-H21 ◽  
Author(s):  
C. S. Bockman ◽  
W. B. Jeffries ◽  
W. A. Pettinger ◽  
P. W. Abel
Keyword(s):  
Mesenteric Artery ◽  
Wistar Rats ◽  
Fold Increase ◽  
Vasopressin Receptor ◽  
Receptor Function ◽  
Salt Treatment ◽  
Threefold Increase ◽  
Lysine Vasopressin ◽  
Salt Hypertension ◽  
Vasopressin Receptors

Mesenteric artery rings from Wistar and Wistar-Furth rats subcutaneously treated with deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water were used to measure endothelial modulation of contractile sensitivity and vasopressin receptor function and affinity. DOCA-salt hypertension reduced contractile sensitivity to arginine vasopressin (AVP) and did not affect contractile sensitivity to norepinephrine in arteries from Wistar rats. Endothelial removal caused a threefold increase in contractile sensitivity to AVP and norepinephrine in DOCA-salt hypertensive Wistar rats. In Wistar-Furth rats, DOCA-salt treatment did not affect contractile sensitivity to AVP, lysine vasopressin, oxytocin, and norepinephrine or the affinity of the vasopressin receptor for agonists or antagonists. Removal of endothelium did not affect vasopressin contractile sensitivity but caused a 15-fold increase in contractile sensitivity to norepinephrine in untreated or DOCA-salt-treated Wistar-Furth rats. These data show that reduced vasopressin receptor function and increased endothelial function that compensate for increased contractile sensitivity in arteries from DOCA-salt hypertensive Wistar rats are not the cause of resistance of DOCA-salt-treated Wistar-Furth rats to the development of enhanced contractile sensitivity and hypertension.

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