RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension

Abstract In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. Key messages The most severe hypertension-induced kidney injury occurs in malignant hypertension. In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades. Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.

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Abstract P212: Kidney Injury Caused By Preeclamptic Pregnancy Improves Postpartum In A Transgenic Rat Model

Hypertension ◽

10.1161/hyp.76.suppl_1.p212 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Sarah M Kedziora ◽

Kristin Kraeker ◽

Lajos Markó ◽

Dominik N Mueller ◽

Ralf Dechend ◽

...

Keyword(s):

Blood Pressure ◽

High Blood Pressure ◽

Rat Model ◽

Cardiac Remodeling ◽

Kidney Injury ◽

Male Rats ◽

Transgenic Rat ◽

Arterial Blood ◽

Pregnancy And Postpartum ◽

Transgenic Rat Model

Preeclamptic pregnancies involve mild renal injuries. However, there has been evidence that women with a history of preeclampsia (PE) have an increased risk to develop kidney disease in association to high blood pressure later in life. This study aims to characterize renal injury during pregnancy and postpartum in an established transgenic rat model for PE. Female Sprague-Dawley rats transgenic for the human angiotensinogen gene develop a PE phenotype in pregnancy, including cardiac remodeling, when mated with male rats harboring the human renin gene. Postpartum, blood pressure restores but cardiac remodeling persists. We hypothesize that PE during pregnancy mediates kidney injuries but does not fully restore after ending of the high blood pressure (postpartum). The renal alterations were analyzed by histological staining, gene expression and urine analysis. PE rats have elevated mean arterial blood pressure during pregnancy (PE d19 148.4 ± 20.7 mmHg) compared to normotensive values in control animals (WT d19 105.3 ± 4.6 mmHg). During PE increased expression of kidney injury marker 1 ( Kim-1/18S : PE d21 4.14 ± 3.26; WT d21 0.08 ± 0.02), neutrophil gelatinase associated lipocalin 2 ( Ngal/18S : PE d21 1.64 ± 0.83; WT d21 0.59 ± 0.28) and connective-tissue growth factor ( Ctgf/18S: PE d21 1.51 ± 0.46; WT d21 0.92 ± 0.32) were detected. Kidneys of PE rats showed mild glomerular (PAS-positive glomerular area PE d21 86.2 ± 4.4%; WT d21 79.1 ± 3.2%) and tubular changes during PE pregnancy resulting in albuminuria (albumin/creatinine ratio PE d19 2193.8 ± 1878.2; WT d19 290.4 ± 252.0). However, 4 weeks after pregnancy (approx. 2 years in humans) most of the PE related renal damages were absent including albuminuria and elevated expression of biomarkers ( Kim-1/18S : PE d50 0.09 ± 0.05; WT d50 0.23 ± 0.13; Ctgf/18S : PE d50 0.78 ± 0.25; WT d50 0.8 ± 0.25; Ngal/18S : PE d50 0.37 ± 0.17; WT 50 0.47 ± 0.11). Only mild enlargement of glomerular tuft area (PE d50 7523.8 ± 418.7 μm 2 ; WT d50 7058.4 ± 198.8 μm 2 ) was detected. Overall, the glomerular and tubular injuries are present during pregnancy in this transgenic PE rat. Most restore postpartum, speculating long-term kidney failure observed in humans is associated to hypertension and additional cardiovascular events.

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SP374CANAGLIFLOZIN, A SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT-2) BLOCKER, NORMALIZES BLOOD GLUCOSE WITHOUT AFFECTING SYSTEMIC BLOOD PRESSURE, OXIDATIVE STRESS, INTRARENAL ANGIOTENSINOGEN GENE EXPRESSION AND KIDNEY INJURY IN TYPE 1 DIABETIC MICE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfw168.01 ◽

2016 ◽

Vol 31 (suppl_1) ◽

pp. i214-i214 ◽

Cited By ~ 2

Author(s):

John S.D. Chan ◽

Isabelle Chenier ◽

Anindya Ghosh ◽

Chin-Han Wu ◽

Chao-Sheng Lo ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Blood Pressure ◽

Blood Glucose ◽

Kidney Injury ◽

Systemic Blood Pressure ◽

Diabetic Mice ◽

Systemic Blood ◽

Angiotensinogen Gene

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Routine Treatment of Epilepsy

Journal of Mental Science ◽

10.1192/bjp.75.308.107 ◽

1929 ◽

Vol 75 (308) ◽

pp. 107-113

Author(s):

John P. Steel

Keyword(s):

Blood Pressure ◽

Differential Diagnosis ◽

High Blood Pressure ◽

List Type ◽

Type Number ◽

Routine Treatment ◽

General Paralysis ◽

Treatment Of Epilepsy ◽

Tabes Dorsalis

In this hospital we have a routine differential diagnosis which is applied in all cases of suspected epilepsy and which is as follows: (a)High blood-pressure.(b)Trauma of vessels and angiospasm.(c)Nephritis, subacute and chronic.(d)Diabetes.(e)Tabes dorsalis, tabo-paresis, neuro-syphilis and general paralysis.(f)Hysteria.(g)Epilepsy.

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Single-cell transcriptomics predicts relapse in MLL-rearranged acute lymphoblastic leukemia in infants

10.1101/2020.04.14.20056580 ◽

2020 ◽

Author(s):

Tito Candelli ◽

Pauline Schneider ◽

Patricia Garrido Castro ◽

Luke A. Jones ◽

Rob Pieters ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

Risk Stratification ◽

Single Cell ◽

Rna Sequencing ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

List Type ◽

Relapse Risk ◽

Single Cell Rna Sequencing

AbstractInfants with MLL-rearranged acute lymphoblastic leukemia (ALL) undergo intense therapy to counter a highly aggressive leukemia with survival rates of only 30-40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. Accurate relapse prediction would enable treatment strategies that take relapse risk into account, with potential benefits for all patients. Through analysis of diagnostic bone marrow biopsies, we show that single-cell RNA sequencing can predict future relapse occurrence. By analysing gene modules derived from an independent study of the gene expression response to the key drug prednisone, individual leukemic cells are predicted to be either resistant or sensitive to treatment. Quantification of the proportion of cells classified by single-cell transcriptomics as resistant or sensitive, accurately predicts the occurrence of future relapse in individual patients. Strikingly, the single-cell based classification is even consistent with the order of relapse timing. These results lay the foundation for risk-based treatment of MLL-rearranged infant ALL, through single-cell classification. This work also sheds light on the subpopulation of cells from which leukemic relapse arises. Leukemic cells associated with high relapse risk are characterized by a smaller size and a quiescent gene expression program. These cells have significantly fewer transcripts, thereby also demonstrating why single-cell analyses may outperform bulk mRNA studies for risk stratification. This study indicates that single-cell RNA sequencing will be a valuable tool for risk stratification of MLL-rearranged infant ALL, and shows how clinically relevant information can be derived from single-cell genomics.Key PointsSingle-cell RNA sequencing accurately predicts relapse in MLL-rearranged infant ALLIdentification of cells from which MLL-rearranged infant ALL relapses occur

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T. violacea lowers blood pressure and down regulates AT1a gene expression in a hypertensive rat model

The FASEB Journal ◽

10.1096/fasebj.21.6.a1247-b ◽

2007 ◽

Vol 21 (6) ◽

Author(s):

Irene Mackraj ◽

Shamal Ramesar ◽

Ravesh Singh

Keyword(s):

Gene Expression ◽

Blood Pressure ◽

Rat Model ◽

Hypertensive Rat

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Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex

10.1101/585430 ◽

2019 ◽

Author(s):

Donna M. Werling ◽

Sirisha Pochareddy ◽

Jinmyung Choi ◽

Joon-Yong An ◽

Brooke Sheppard ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Rna Sequencing ◽

Protein Interactions ◽

Developmental Trajectories ◽

Neuropsychiatric Disorder ◽

Integrated Analysis ◽

List Type ◽

Whole Genome ◽

Specific Expression

SummaryVariation in gene expression underlies neurotypical development, while genomic variants contribute to neuropsychiatric disorders. BrainVar is a unique resource of paired whole-genome sequencing and bulk-tissue RNA-sequencing from the human dorsolateral prefrontal cortex of 176 neurotypical individuals across prenatal and postnatal development, providing the opportunity to assay genomic and transcriptomic variation in tandem. Leveraging this resource, we identified rare premature stop codons with commensurate reduced and allele-specific expression of corresponding genes, and common variants that alter gene expression (expression quantitative trait loci, eQTLs). Categorizing eQTLs by prenatal and postnatal effect, genes affected by temporally-specific eQTLs, compared to constitutive eQTLs, are enriched for haploinsufficiency, protein-protein interactions, and neuropsychiatric disorder risk loci. Expression levels of over 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell type specific genes and neuropsychiatric disorder loci, underscoring the importance of cataloguing developmental trajectories in understanding cortical physiology and pathology.HighlightsWhole-genome and RNA-sequencing across human prefrontal cortex development in BrainVarGene-specific developmental trajectories characterize the late-fetal transitionIdentification of constitutive, prenatal-specific, postnatal-specific, and rare eQTLsIntegrated analysis reveals genetic and developmental influences on CNS traits and disorders

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Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus

American Journal of Nephrology ◽

10.1159/000499597 ◽

2019 ◽

Vol 49 (4) ◽

pp. 331-342 ◽

Cited By ~ 32

Author(s):

T. Cooper Woods ◽

Ryousuke Satou ◽

Kayoko Miyata ◽

Akemi Katsurada ◽

Courtney M. Dugas ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

High Blood Pressure ◽

Kidney Injury ◽

Renal Tubules ◽

Glucose Levels

Background: Hypertension and renal injury are common complications of type 2 diabetes mellitus (T2DM). Hyperglycemia stimulates renal proximal tubular angiotensinogen (AGT) expression via elevated oxidative stress contributing to the development of high blood pressure and diabetic nephropathy. The sodium glucose cotransporter 2 (SGLT2) in proximal tubules is responsible for the majority of glucose reabsorption by renal tubules. We tested the hypothesis that SGLT2 inhibition with canagliflozin (CANA) prevents intrarenal AGT augmentation and ameliorates kidney injury and hypertension in T2DM. Methods: We induced T2DM in New Zealand obese mice with a high fat diet (DM, 30% fat) with control mice receiving regular fat diet (ND, 4% fat). When DM mice exhibited > 350 mg/dL blood glucose levels, both DM- and ND-fed mice were treated with 10 mg/kg/day CANA or vehicle by oral gavage for 6 weeks. We evaluated intrarenal AGT, blood pressure, and the development of kidney injury. Results: Systolic blood pressure in DM mice (133.9 ± 2.0 mm Hg) was normalized by CANA (113.9 ± 4.0 mm Hg). CANA treatment ameliorated hyperglycemia-associated augmentation of renal AGT mRNA (148 ± 21 copies/ng RNA in DM, and 90 ± 16 copies/ng RNA in DM + CANA) and protein levels as well as elevation of urinary 8-isoprostane levels. Tubular fibrosis in DM mice (3.4 ± 0.9-fold, fibrotic score, ratio to ND) was suppressed by CANA (0.9 ± 0.3-fold). Furthermore, CANA attenuated DM associated increased macrophage infiltration and cell proliferation in kidneys of DM mice. Conclusions: CANA prevents intrarenal AGT upregulation and oxidative stress and which may mitigate high blood pressure, renal tubular fibrosis, and renal inflammation in T2DM.

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No evidence for HPA reset in adult sheep with high blood pressure due to short prenatal exposure to dexamethasone

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00222.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. R343-R350 ◽

Cited By ~ 17

Author(s):

Miodrag Dodic ◽

Arianne Peers ◽

Karen Moritz ◽

Vicky Hantzis ◽

E. Marelyn Wintour

Keyword(s):

Gene Expression ◽

Blood Pressure ◽

High Blood Pressure ◽

Hpa Axis ◽

Receptor Gene ◽

Adult Offspring ◽

Significant Difference ◽

Group D ◽

Receptor Gene Expression ◽

Concentration Curves

Exposure of pregnant ewes to dexamethasone, for only 2 days (term ∼150 days) at 27 days of gestation ( group D), results in adult offspring with high blood pressure. In this study, hemorrhage stress has been used to see whether in these animals the responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis is altered. In addition, we studied mineralocorticoid (MR) and glucocorticoid (GR) receptor gene expression in the hippocampus and GR gene expression in the hypothalamus using real-time PCR. Calculated areas under the adrenocorticotropin, arginine vasopressin, and cortisol plasma concentration curves in response to hemorrhage were similar between the control and group D. In addition, there was no significant difference in the expression of MR and GR in the hippocampus or GR in the hypothalamus between the control and group D. Taken together, it is unlikely that reset in the HPA axis plays a major role in this particular model of “programmed” hypertension.

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