Bruce Hendry - Academia.edu (original) (raw)

Papers by Bruce Hendry

BMC Nephrology

Background T-type calcium channels (TTCC) are involved in mesangial cell proliferation. In acute ... more Background T-type calcium channels (TTCC) are involved in mesangial cell proliferation. In acute thy-1 nephritis in the rat TTCC inhibition reduces glomerular damage and cell proliferation. This work is extended here by a study of the non-selective TTCC inhibitor TH1177 in a chronic model of proliferative glomerulonephritis (GN) including late treatment starting after the initial inflammation has resolved. The objective was to determine the effects of TH1177 in a model of chronic mesangioproliferative renal disease. Methods Chronic GN was induced in WKY rats by unilateral nephrectomy (day − 7) followed by day 0 injection of Ox7 thy-1 mAb. Treatment with TH1177 (10–20 mg/Kg daily IP) was started on day 2 (early treatment) or on day 14 (late treatment) and compared to vehicle-treated controls until sacrifice at day 42. Glomerular disease was assessed with a damage score, fibrosis assay, cellular counts and renal function measured by serum creatinine. Results Treatment with TH11777 was...

Journal of the American Society of Nephrology, 1999

Progressive renal fibrosis is driven by a range of cytokines that act via membrane receptors and ... more Progressive renal fibrosis is driven by a range of cytokines that act via membrane receptors and intracellular signaling cascades to evoke gene transcription events and related responses. The Ras family of GTPases has been implicated in many of these signaling cascades in model systems such as 3T3 fibroblasts. However, the role of the specific Ras isoforms Ki, Ha, and N in the stimulation of renal fibroblasts has not been defined. In this study, Ras has been inhibited in primate renal fibroblasts (vero cells) using specific phosphorothioate oligodeoxynucleotides (oligos) targeting the three isoforms. Lipofectin transfection with 200 to 400 nM Ki-Ras oligo inhibited the epidermal growth factor-and fibroblast growth factor-stimulated proliferation of vero cells by 25 to 35% with a lesser effect on serum-stimulated growth. Oligos against Ha-Ras and N-Ras were inactive with respect to control oligo. Total cellular Ras protein (estimated by Western blotting) was reduced by 60 to 90% 24 h after transfection with Ki-Ras oligo. N-Ras, Ha-Ras, and control oligos were inactive. Total Ras synthesis over 4 h measured using [ 35 S]-cys/met pulse chase was reduced by approximately 70% by Ki-Ras oligo and not altered by other oligos. The fractional prenylation of Ras was quantified from the discrete bands on polyacrylamide gel electrophoresis and was increased by the Ki-Ras oligo alone. These data demonstrate that these renal fibroblasts predominantly express the Ki isoform of Ras and that this GTPase plays a role in the stimulated proliferation of these cells. Ras GTPases may be a target for the inhibition of processes leading to renal fibrosis.

iScience, 2021

HIGHLIGHTS Following AKI, markers of fibrosis and inflammation go up simultaneously AKI is associ... more HIGHLIGHTS Following AKI, markers of fibrosis and inflammation go up simultaneously AKI is associated with reduced fatty acid oxidation and oxidative phosphorylation Changes in metabolism persist as chronic kidney disease develops Changes in metabolism are associated with increased serum levels of triglycerides

World Journal of Traditional Chinese Medicine, 2019

Botanicals are broadly defined as materials derived from plants and the term particularly refers ... more Botanicals are broadly defined as materials derived from plants and the term particularly refers to medicinal plants (herbs), herbal materials, herbal preparations, and finished herbal products that contain parts of plants as active ingredients and are used as herbal medicines or functional food. In past decades, globalization has accelerated exchanges of herbal traditions, and herbal medicines have gained popularity worldwide and become more important to the medical and pharmaceutical community, as well as to the public. [1,2] Also known as botanical medicine, phytomedicine, or phytotherapy, herbal medicines have deep cultural roots and long historic records of use in humans. These materials are arguably the most important part of traditional medicine. [3,4] Indeed, herbal medicines have some drug-like properties, are a rich resource and knowledge base for new drugs, and offer new options for unmet medical needs. [5,6] In keeping with this, regulators worldwide have increasingly approved and regulated herbal medicines as drugs. [7,8] However, herbal medicines, and other traditional medicines, can be both friends and foes to the kidneys, as elegantly reviewed by Wojcikowski et al. [9,10] and most recently by Stanifer et al. [11] The US National Kidney Foundation has suggested renal patients to "avoid all herbal supplements," especially 17 potential nephrotoxic herbs and over 50 phosphate-or potassium-rich herbs. [12] While acknowledging the potential for harm, we feel that there is potential clinical and scientific value for herbal medicines in prevention and treatment of acute kidney injury (AKI) [13] and chronic kidney disease (CKD), [14,15]

Nephrology Dialysis Transplantation, 2016

Background. The pathogenesis and natural history of HIVassociated immune complex kidney disease (... more Background. The pathogenesis and natural history of HIVassociated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. Methods. In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. Results. Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. Conclusions. These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.

Recent Advances in Theories and Practice of Chinese Medicine, 2012

In vivo models are invaluable research tools but not without its limitation, especially in the de... more In vivo models are invaluable research tools but not without its limitation, especially in the development of drugs targeting fibrosis given the complex aetiologies and inflammatory processes involved in this pathological condition. In particular, drug leads displaying effectiveness in in vivo models of fibrosis may stem from (i) inhibition of the primary aetiological factors, (ii) inhibition of inflammation, a common inciting factor of fibrosis, (iii) inhibition of fibrosis per se, or (iv) a net effect of any combinations of the aforementioned. For the initial development of drugs with specific anti-fibrotic effects independent of antiinflammatory actions and any specific aetiological factors, in vitro models of fibrosis appear to be more appropriate. Our laboratory recently reported transforming growth factor-1 (TGF-1)-induced inflammation-free in vitro models of fibrosis in mesenchymal cells, featuring 2-dimentional (2D) ECM protein accumulation reflecting net collagen accumulation, and 3-dimentional (3D) nodular formation following ECM protein-induced disruption of cell monolayer, which can both be objectively quantified. By coating specific matrix on 96-well plates, which determines the 2D or 3D nature of the models, we are able to quantify readouts more reliably, permitting high-throughput screening of compounds with anti-fibrotic activities (Xu et al., 2007). In contrast to the lack of "anti-fibrotics" in Western medicine clinics, there is accumulating evidence suggesting anti-fibrotic effects of Chinese materia medicas (CMMs), i.e., medicinal materials used in traditional Chinese medicine (TCM) (Hu et al., 2007). However, most of these conclusions were drawn from animal models or patients and hence it was not clear whether the reported efficacy of those CMMs was secondary to inhibition of aetiological factors or inflammation, or whether they exerted genuine anti-fibrotic activities (Hu et al., 2009). We hypothesised that at least some of the "anti-fibrotic" herbal derivatives reported in the literature are indeed anti-fibrotic by antagonising TGF-1-specific pro-fibrotic pathways or common pathways of fibrosis. By employing the 2D in vitro model (Xu et al., 2007), we tested the anti-fibrotic activity of 21 CMM-derived compounds, 11 methanolic extracts of single CMMs and 27 formulae that contained two or more CMMs as mixtures, and found that five compounds, three single CMM extracts and 16 formulae had in vitro anti-fibrotic activities (Hu et al., 2009). Among the five CMM-derived compounds, three flavonoids (quercetin, baicalin and baicalein) showed similar dose-dependent in vitro antifibrotic activities while two non-flavonoids (salvianolic acid B and emodin) showed varied in vitro anti-fibrotic activities with poor dose dependency. Among the three CMM extracts showing significant in vitro anti-fibrotic activities, Huangqin (root of Scutellaria baicalensis Georgi) is rich in baicalin and baicalein, Danshen (root of Salvia miltiorrhiza Bunge) is rich in salvianolic acid B and Dahuang (root of Rheum palmatum L.) is rich in emodin. Among the 16 herbal formulae with in vitro anti-fibrotic effects, eight contained neither Huangqin, Danshen nor Dahuang, while the remaining eight contained at least one of the three CMMs (Hu et al., 2009). Following successful identification of in vitro anti-fibrotic activities in herbal entities, we have extended our work to focus on TCM knowledge-based discovery of novel anti-fibrotic drug leads from natural sources, especially CMMs. In TCM, fibrosis is diagnosed as a kind of "Jie Zheng" which means "lump or clot". Based on this concept, two senior TCM practitioners were invited to choose a collection of 27 CMMs, including 26 medicinal plant parts and one medicinal fungus, which they would consider using in patients with fibrotic diseases. Based on the traditional categories of CMMs, the 27 CMMs fall into three functional subgroups, namely "Huo Xue Hua Yu" ("promoting the circulation and resolving www.intechopen.com Knowledge-Based Discovery of Anti-Fibrotic and Pro-Fibrotic Activities from Chinese Materia Medica 339 the clot"), "Hua Tan" ("resolving the sputum") and "Bu Xu" ("tonifying the deficiency"), where "clot" and "sputum" in TCM do not mean the same as the terms in Western medicine. In addition to the 27 CMMs, Chuanwutou, an unprocessed herb with well-known toxic effects, was also tested to serve as a control for cytotoxic effects, if any. In fact, owing to its strong "Qu Feng Shi" ("dispelling the wind and damp" or anti-rheumatic function) property, Chuanwutou is rather commonly prescribed to patients with diseases complicated by fibrosis, although only processed Chuanwutou is allowed for clinical use. The aim of this project was to examine the in vitro anti-fibrotic and pro-fibrotic activities of these 28 CMMs (Table 1) and herein we report that eight CMMs (Baibeiyegen, Liedang, Gusuibu, Jixueteng, Lingzhi, Meiguiqie, Moyao and Shiliuhua) have in vitro anti-fibrotic activities while three (Chuanwutou, Dangshen and Yimucao) have pro-fibrotic activities. 2. Materials and methods 2.1 CMMs and extraction methods Liedang was authenticated according to the criteria described in Jilin Zhongcaoyao

Manual of Pediatric Nephrology, 2013

ABSTRACT Kidney disease is an important complication of HIV infection. Antiretroviral therapy has... more ABSTRACT Kidney disease is an important complication of HIV infection. Antiretroviral therapy has dramatically improved the life expectancy of HIV-infected patients with end-stage renal disease. Renal replacement therapy, including kidney transplantation, should be offered to HIV-positive patients.

PLoS ONE, 2011

Background: Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible ... more Background: Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible role in kidney development by activating retinoic acid receptors. Although the location, concentration and roles of endogenous retinoic acid in postnatal kidneys are poorly defined, there is accumulating evidence linking post-natal vitamin A deficiency to impaired renal concentrating and acidifying capacity associated with increased susceptibility to urolithiasis, renal inflammation and scarring. The aim of this study is to examine the presence and the detailed localization of endogenous retinoic acid activity in neonatal, young and adult mouse kidneys, to establish a fundamental ground for further research into potential target genes, as well as physiological and pathophysiological roles of endogenous retinoic acid in the post-natal kidneys. Methodology/Principal Findings: RARE-hsp68-lacZ transgenic mice were employed as a reporter for endogenous retinoic acid activity that was determined by X-gal assay and immunostaining of the reporter gene product, b-galactosidase. Double immunostaining was performed for b-galactosidase and markers of kidney tubules to localize retinoic acid activity. Distinct pattern of retinoic acid activity was observed in kidneys, which is higher in neonatal and 1-to 3-week-old mice than that in 5-and 8-week-old mice. The activity was present specifically in the principal cells and the intercalated cells of the collecting duct system in all age groups, but was absent from the glomeruli, proximal tubules, thin limbs of Henle's loop and distal tubules. Conclusions/Significance: Endogenous retinoic acid activity exists in principal cells and intercalated cells of the mouse collecting duct system after birth and persists into adulthood. This observation provides novel insights into potential roles for endogenous retinoic acid beyond nephrogenesis and warrants further studies to investigate target genes and functions of endogenous retinoic acid in the kidney after birth, particularly in the collecting duct system.

Nephrology Dialysis Transplantation, 2003

Background. Small monomeric Ras GTPases play critical and specific roles in the control of cellul... more Background. Small monomeric Ras GTPases play critical and specific roles in the control of cellular proliferation and apoptosis but the expression of the three Ras isoforms (Ha-Ras, Ki-Ras and N-Ras) in human renal tissue is unknown. This work is an immunohistochemical study of Ras expression in normal renal tissue and in membranous glomerulonephritis (MGN), IgA nephropathy (IgAN) and IgAnegative mesangioproliferative glomerulonephritis (MPGN). Methods. Formalin-fixed, paraffin-embedded tissue was stained using pan-Ras monoclonal antibody (mAb) and Ras isoform-specific mAb. Detection employed a (DAKO Envision) modified polymer system. Results. The expression of Ras isoforms in normal human kidney was cell-specific. For example, N-Ras was detected in tubule epithelial cells but not in glomerular or interstitial cells. Ki-Ras was expressed in mesangial cells, interstitial cells and in proximal convoluted tubule cells (PCT) (particularly localized at brush borders) and in collecting duct cells (CD) (localized to cell membranes) but not in podocytes. Cytoplasmic Ha-Ras was detected in all the above cell types except podocytes. MGN was associated with podocyte expression of all three Ras isoforms and with reduced mesangial cell expression of Ha-Ras and Ki-Ras. IgAN was characterized by podocyte expression of Ha-Ras (but not Ki-Ras) and reduced mesangial cell expression of Ki-Ras without alterations in mesangial Ha-Ras expression. MPGN was associated with reduced mesangial cell Ha-Ras and Ki-Ras expression without significant podocyte Ras expression. Conclusion. These disease-specific and isoform-specific alterations in Ras expression may be of significance in pathogenesis and warrant further functional investigation.

Nephrology Dialysis Transplantation, 2009

Background. Renal impairment post-liver transplant (LT) is often attributed to calcineurin inhibi... more Background. Renal impairment post-liver transplant (LT) is often attributed to calcineurin inhibitors (CNIs). A renal biopsy can be a useful tool but may be complicated in LT recipients. We aimed to determine the clinical scenarios that prompted a decision to perform a renal biopsy in this patient population, to assess histological findings and evaluate patient management and survival and renal outcome. Methods. Information on clinical variables and renal histology was extracted from single-centre prospectively compiled databases from 1996 onwards.

Nephrology Dialysis Transplantation, 2008

Kidney International, 2006

In previous work, we have demonstrated that Ras GTPases regulate proliferation in a range of huma... more In previous work, we have demonstrated that Ras GTPases regulate proliferation in a range of human renal cells. The present work compares human and mouse mesangial cell (HMC and MMC) responses to specific knockdown of Ras genes with antisense oligonucleotides (AS-oligos), and examines the role of the p21 (cip1) and p27 (kip1) cyclin-dependent kinase inhibitors in these responses in mouse cells. HMC and MMC were lipofectin transfected with ras-targeted AS-oligo at 200-400 nM for 18 h followed by growth of cells in 20% serum for 18-72 h. Cell proliferation was assessed with an MTS assay and bromodeoxyuridine (BrdU) uptake. Apoptosis was quantified using nuclear stain with Hoechst 33342 dye. In MMC, Ha-ras AS-oligo caused an increase in apoptosis from o2% to 10-15% of cells after 18 h in serum (Po0.01). Control, Ki-ras and N-ras AS-oligos had minimal effects on apoptosis. BrdU uptake studies showed that BrdU þ ve MMC were increased by 20-40% (Po0.05) after Ha-ras AS-oligo at 24 h; other ras AS-oligos were inactive. HMC number was reduced by 40-80% (Po0.01) at 48-72 h by both Ha-ras and Ki-ras AS-oligos. These actions were associated with reductions in BrdU þ ve cells. In HMC, the ras AS-oligos did not induce apoptosis. p21(À,À) MMC showed exaggerated apoptotic responses to Ha-Ras AS-oligo. In mouse cells, Ha-Ras expression appears necessary to prevent apoptotic cell death; Ras expression does not appear necessary for cells to progress through the cell cycle. In human cells, Ras does not appear necessary to prevent apoptosis but Ha-Ras and Ki-Ras appear to be required for cell cycle progression.

Journal of the American Society of Nephrology, 2003

Control of glomerular blood flow is complex, crucial in renal pathophysiology, and an attractive ... more Control of glomerular blood flow is complex, crucial in renal pathophysiology, and an attractive target for therapeutic intervention. In this issue of JASN, Cavarape et al. (1) observe that inhibition of Rho-kinase leads to a decrease in basal tone of the glomerular afferent and efferent arterioles associated with a rise in glomerular blood flow in the split hydronephrotic rat kidney model. Moreover, Rho-kinase inhibition also antagonized the actions of three distinct vasoconstrictors: an endothelin B receptor agonist, a guanylyl cyclase inhibitor, and an adenosine A 1 receptor agonist. This represents one of the first applications in the kidney of the seminal demonstration by Uehata et al. (2) that Rho GTPases play a vital role in smooth muscle contraction in vivo and brings attention to the very rapid advances that are being made in the whole field of cell signaling and renal disease. Cells rely on complex networks of signaling pathways to translate extracellular stimuli into cellular events such as mechanical responses, gene transcription, protein translation, and cell proliferation. Most signaling cascades are activated by the

Journal of Ethnopharmacology, 2012

Hypertension, 1990

Human mesangial cells in culture proliferate in response to platelet-derived growth factor (PDGF)... more Human mesangial cells in culture proliferate in response to platelet-derived growth factor (PDGF) and thrombin. Both of these agents also induce changes in cytosolic calcium that are dependent on both mobilization of intracellular calcium and influx of extracellular calcium. We hypothesized that calcium channel blockers, by preventing influx of extracellular calcium, may inhibit proliferation induced by these mitogens. We found that three different calcium channel blockers, diltiazem, nifedipine, and verapamil, were able to significantly inhibit [3H]thymidine incorporation into human mesangial cells induced by either PDGF or thrombin. The inhibitory effect of these agents was significant at 10(-5) M. The calcium channel blockers also attenuated the increases in cell number and percentage of labeled nuclei induced by these mitogens. In contrast, dantrolene, an inhibitor of intracellular calcium mobilization, had no significant effect on [3H]thymidine incorporation by PDGF or thrombin...

Clinical Infectious Diseases, 2008

patients [1-3]. The reported prevalence of HIVAN in this population has a range of 3.5%, as deter... more patients [1-3]. The reported prevalence of HIVAN in this population has a range of 3.5%, as determined by results of screens for proteinuria, to 12%, as determined by postmortem studies [4, 5]. Most studies of HIVAN originate in the United States, where HIVAN is associated with advanced immune suppression, a high proteinuria level, and rapid progression to end-stage renal disease (ESRD) [3, 6]. Before the availability of antiretroviral therapy (ART), the prognosis for patients with HIVAN was poor and was generally measured in weeks to months [7-9].

Clinica Chimica Acta, 2001

There is increasing evidence that extracellular ATP acting on purinoceptors may play an important... more There is increasing evidence that extracellular ATP acting on purinoceptors may play an important signalling role in renal 21 epithelial cells, often through alterations in cellular Ca. In this paper effects of extracellular ATP and related purinoceptor 21 agonists and antagonists on [Ca ] have been studied in single cells from primary cultures of rat proximal tubule cells. i 21 Responses to 1-100 mmol / l ATP were heterogeneous; 55% of cells showed a transient rise in [Ca ] , 20% of cells showed i 21 a transient fall; in 25% there was no response. ATP actions on [Ca ] were abolished by pre-treatment with thapsigargin. i 21 The P receptor antagonist suramin unexpectedly increased the [Ca ] response to ATP; the related antagonist XAMR 0721 2 i did not significantly alter ATP responses. This difference is likely to arise from the inhibition of ATP hydrolysis by suramin. UTP, ADP and the non-hydrolyzable ATP analogue adenosine-59-O-(3-thio)-triphosphate (ATPgS)produced similar 21 21 increases in [Ca ]. The magnitude of the [Ca ] responses to 100 mmol / l agonist gave an agonist potency order of i i ATP$ADP$UTP¯ATPgS. Desensitisation experiments demonstrated the presence of more than one P2Y ATP receptor subtype on a single cell. These results are consistent with the expression of purinoceptors of both P2Y and P2Y subclasses 1 2 on individual rat proximal tubule cells coupled to inositol trisphosphate-mediated release of intracellular calcium stores.

Carbohydrate Research, 2004

The micro-heterogeneity of human serum IgA1 results from variable O-glycan substitutions in the &... more The micro-heterogeneity of human serum IgA1 results from variable O-glycan substitutions in the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;hinge region&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; of the molecule and this O-glycosylation may be altered in a number of medical conditions. This micro-heterogeneity has been monitored by analysis of IgA1-derived tryptic O-glycopeptides using matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-ToF-MS) analysis. With ammonium citrate-trihydroxyacetophenone matrix, individual compositional glycoforms have been baseline resolved in more than 70 samples and these spectra revealed for the first time that, in addition to expected substitution with 3,4 and 5 GalNAcs, a sixth GalNAc substitution was also present in the hinge region of the molecule. The spectra obtained from subsequent exoglycosidase-treated samples confirmed hexa-O-substitution. Following endoprotease digestions of the exoglycosidase treated samples, possible locations for the sixth GalNAc were indicated from further MALDI-ToF-MS analysis. Hexa-substitution accounts for around 5-10% the glycoforms. This is, we believe, the first report of hexa-O-substitution with GalNAc of human serum IgA1.