Papers by Joseph Bonventre
Molecular and Cellular Biology, 2001
The group IV cytosolic phospholipase A 2 (cPLA 2 ) has been localized to the nucleus (M. R. Sierr... more The group IV cytosolic phospholipase A 2 (cPLA 2 ) has been localized to the nucleus (M. R. Sierra-Honigmann, J. R. Bradley, and J. S. Pober, Lab. Investig. 74:684–695, 1996) and is known to translocate from the cytosolic compartment to the nuclear membrane (S. Glover, M. S. de Carvalho, T. Bayburt, M. Jonas, E. Chi, C. C. Leslie, and M. H. Gelb, J. Biol. Chem. 270:15359–15367, 1995; A. R. Schievella, M. K. Regier, W. L. Smith, and L. L. Lin, J. Biol. Chem. 270:30749–30754, 1995). We hypothesized that nuclear proteins interact with cPLA 2 and participate in the functional effects of this translocation. We have identified a nuclear protein, cPLA 2 -interacting protein (PLIP), a splice variant of human Tip60, which interacts with the amino terminal region of cPLA 2 . Like Tip60, PLIP cDNA includes the MYST domain containing a C2HC zinc finger and well-conserved similarities to acetyltransferases. Both PLIP and Tip60 coimmunoprecipitate and colocalize with cPLA 2 within the nuclei of t...
Journal of the American Society of Nephrology, 2019
Senescent cells have undergone permanent growth arrest, adopt an altered secretory phenotype, and... more Senescent cells have undergone permanent growth arrest, adopt an altered secretory phenotype, and accumulate in the kidney and other organs with ageing and injury. Senescence has diverse physiologic roles and experimental studies support its importance in nephrogenesis, successful tissue repair, and in opposing malignant transformation. However, recent murine studies have shown that depletion of chronically senescent cells extends healthy lifespan and delays age-associated disease—implicating senescence and the senescence-associated secretory phenotype as drivers of organ dysfunction. Great interest is therefore focused on the manipulation of senescence as a novel therapeutic target in kidney disease. In this review, we examine current knowledge and areas of ongoing uncertainty regarding senescence in the human kidney and experimental models. We summarize evidence supporting the role of senescence in normal kidney development and homeostasis but also senescence-induced maladaptive r...
Current Opinion in Nephrology and Hypertension, 2019
Purpose of the Review: Acute kidney injury (AKI) remains a major unmet medical need and associate... more Purpose of the Review: Acute kidney injury (AKI) remains a major unmet medical need and associates with high morbidity, mortality, and healthcare costs. Among survivors, long-term outcomes of AKI can include development of chronic kidney disease (CKD) or progression of preexisting CKD. In this review, we focus on ongoing efforts by the AKI community to understand the human AKI to CKD continuum, with an emphasis on the cellular stress responses that underlie AKI and the maladaptive responses that persist in the acute to chronic phase. The emphasis is on work that has been published in the past year in this rapidly expanding field. Recent Findings: Recent studies in preclinical models highlight the importance of mitochondrial dysfunction, cell death and inflammation in the underlying pathogenesis of AKI. These pathogenic mechanisms can resolve with adaptive kidney repair but persist in maladaptive repair that leads to progressive chronic disease. The complexity and interconnections of these pathways involve cross-talk between the tubular epithelium, endothelium and interstitial compartments. Summary: Approaches which lessen or counteract these cellular responses represent novel strategies to prevent AKI and stop or slow down the progression to CKD.
Science Translational Medicine, 2019
Cyclin G1 regulates G 2 -M arrest in proximal tubular cells, promoting a TASCC-induced secretory ... more Cyclin G1 regulates G 2 -M arrest in proximal tubular cells, promoting a TASCC-induced secretory phenotype, fibrosis, and kidney disease progression.
Lancet (London, England), Feb 25, 2017
Kidney International, 2017
NGAL/Cr, mg/g, median (IQR) 12.75 (3.89-46.19) NAG/Cr, U/g, median (IQR) 4.03 (2.41-7.29) L-FABP/... more NGAL/Cr, mg/g, median (IQR) 12.75 (3.89-46.19) NAG/Cr, U/g, median (IQR) 4.03 (2.41-7.29) L-FABP/Cr, mg/g, median (IQR) 7.31 (1.88-28.11) ACR, albumin/creatinine ratio; BP, blood pressure; Cr, creatinine; eGFR, estimated glomerular filtration rate; IQR, interquartile range; KIM-1, kidney injury molecule-1; L-FABP, liver fatty acid binding protein; NGAL, neutrophil gelatinase-associated lipocalin; NAG, N-acetyl-b-D-glucosaminidase. C-y Hsu et al.: Biomarkers and CKD progression c l i n i c a l i n v e s t i g a t i o n
Nature biotechnology, Jan 12, 2015
Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regen... more Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regeneration, disease modeling and drug screening. We report an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2(+)SALL1(+)WT1(+)PAX2(+) NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8(+)LHX1(+) renal vesicles that self-organize into nephron structures. In both two- and three-dimensional culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidne...
Stem Cells International, 2012
Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per y... more Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative propertiesin vitroandin vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed tha...
Toxicological Sciences, 2007
A multi-age rat model was used to identify potential age-related differences in renal injury foll... more A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg 21 body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten-and 40-day-old rats given 100 mkd of GM for 6-or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10-and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.
Critical Care Medicine, 2008
Objective-Sepsis-induced organ dysfunctions remain prevalent and account for >50% of intensive ca... more Objective-Sepsis-induced organ dysfunctions remain prevalent and account for >50% of intensive care unit admissions for acute renal failure with a mortality rate nearing 75%. In addition to the fact that the mechanisms underlying the pathophysiology of sepsis-related acute renal failure are unclear, the impact on septic-induced acute renal failure of either norepinephrine, a gold-standard vasopressor, and arginine vasopressin, a candidate alternative, are not well understood. Design-Randomized and controlled in vivo study. Setting-Research laboratory and animal facilities. Subjects-Adult rats treated with endotoxin (lipopolysaccharide) and/or vasopressors. Interventions-Rats were intraperitoneally injected with lipopolysaccharide (12 mg/kg) or saline and then infused with either saline, 0.375 μg/μL arginine vasopressin, or 32.5 μg/μL norepinephrine for 18 hrs. These vasopressor rates yielded respective targeted blood levels observed in human septic shock.
Clinical and Translational Science, 2008
Acute kidney injury (AKI) is associated with high morbidity and mortality. The lack of sensitive ... more Acute kidney injury (AKI) is associated with high morbidity and mortality. The lack of sensitive and specific injury biomarkers has greatly impeded the development of therapeutic strategies to improve outcomes of AKI.The unique objective of this study was to evaluate the diagnostic performance of nine urinary biomarkers of AKI—kidney injury molecule‐1 (KIM‐1), neutrophil gelatinase associated lipocalin (NGAL), interleukin‐18 (IL‐18), hepatocyte growth factor (HGF), cystatin C (Cys), N‐acetyl‐β‐D‐glucosaminidase (NAG), vascular endothelial growth factor (VEGF), chemokine interferon‐inducible protein 10 (IP‐10; CXCL10), and total protein—in a cross‐sectional comparison of 204 patients with or without AKI.Median urinary concentrations of each biomarker were significantly higher in patients with AKI than in those without AKI (p < 0.001). The area under the receiver operating characteristics curve (AUC‐ROC) for the combination of biomarkers using a logic regression model [risk score o...
Circulation, 2012
The article by Er et al 10 that is the subject of this editorial was published in the July 17 iss... more The article by Er et al 10 that is the subject of this editorial was published in the July 17 issue of Circulation.
American Journal of Physiology-Renal Physiology, 2006
Recent studies from our laboratory have shown that the mineralocorticoid receptor (MR) blockade w... more Recent studies from our laboratory have shown that the mineralocorticoid receptor (MR) blockade with spironolactone (Sp) prevented renal dysfunction and reduced renal injury in both acute and chronic cyclosporine (CsA) nephrotoxicity. This study was designed to evaluate whether Sp administration reduces functional and structural renal damage associated in the setting of preexisting chronic CsA nephrotoxicity. Twenty eight male Wistar rats were fed a low-sodium diet. Fourteen received vehicle (V) and the others were treated with CsA (15 mg/kg sc). After 18 days one half of each group received Sp (20 mg/kg po) for the subsequent 18 days. Creatinine clearance, arteriolopathy, tubulointerstitial fibrosis, arteriolar thickening, glomerular diameter, apoptosis index and TGF-β, procaspase-3, and kidney injury molecule 1 (Kim-1) mRNA levels as well as Kim-1 shedding in urine were evaluated. Sp reduced the progression of renal dysfunction and tubulointerstitial fibrosis in preexisting chroni...
The American Journal of Pathology, 2010
American Journal of Nephrology, 1996
Urinary N-acetyl-β -D-glucosaminidase (NAG) is a sensitive indicator of renal tubular injury. The... more Urinary N-acetyl-β -D-glucosaminidase (NAG) is a sensitive indicator of renal tubular injury. The aim of the study is to determine the status of urinary NAG excretion in Chinese children with insulin-dependent diabetes mellitus (IDDM) but without any clinical evidence of nephropathy, and to try to find the possible associated factors of such tubular injury if any. Thirty-one children (8 males
American Journal of Physiology-Renal Physiology, 1999
Recovery of the kidney from acute renal failure relies on a sequence of events including epitheli... more Recovery of the kidney from acute renal failure relies on a sequence of events including epithelial cell dedifferentiation and proliferation followed by differentiation and restoration of the functional integrity of the nephron. The factors responsible for, and the significance of, reversion to a less differentiated cell phenotype and its relationship to the proliferative response after ischemia are poorly understood. In an attempt to identify adhesion molecules that may be influential in the recovery process, the expression of neural cell adhesion molecule (NCAM) and markers of epithelial differentiation and proliferation were analyzed at various times after an ischemic insult. In maturing nephrons, NCAM is detectable by immunohistochemistry in renal vesicles, S-shaped bodies, and early tubules. There is minimal cellular NCAM expression in normal tubules of the adult kidney. In contrast, in postischemic kidneys, NCAM expression is abundant in S3 proximal tubule cells 5 days after r...
Nephrology Dialysis Transplantation, 2009
Toxicology and Applied Pharmacology, 2009
As a result of the widespread use of Cd in industry and its extensive dissemination in the enviro... more As a result of the widespread use of Cd in industry and its extensive dissemination in the environment, there has been considerable interest in the identification of early biomarkers of Cd-induced kidney injury. Kim-1 is a transmembrane glycoprotein that is not detectable in normal kidney, but is upregulated and shed into the urine following ischemic or nephrotoxic injury. Recent studies utilizing a sub-chronic model of Cd exposure in the rat have shown that Kim-1 is an early urinary marker of Cd-induced kidney injury. Kim-1 was detected in the urine 4-5 weeks before the onset of proteinuria and 1-3 weeks before the appearance of urinary metallothionein and Clara cell protein 16, which are standard markers of Cd nephrotoxicity. In the present study, we have compared the time course for the appearance of Kim-1 in the urine with the time course for the appearance of alpha glutathione-S-transferase (α-GST), N-acetyl-β-D-glucoseamidase (NAG) and Cd, each of which have been used or proposed as urinary markers of Cd nephrotoxicity. Adult male Sprague-Dawley rats were given daily subcutaneous injections of 0.6 mg (5.36 μmoles)/kg Cd, 5 days per week for up to 12 weeks. One day each week, 24 hour urine samples were collected and analyzed for protein, creatinine and the various markers. The results showed that significant levels of Kim-1 appeared in the urine as early as 6 weeks into the treatment protocol and then continued to rise for the remainder of the 12 week treatment period. By contrast, significant levels of α-GST and NAG did not appear in the urine until 8 and 12 weeks, respectively, while proteinuria was not evident until 10 weeks. The urinary excretion of Cd was below the level of detection until week 4 and then showed a slow, linear increase over the next 6 weeks before increasing markedly between weeks 10 and 12. These results provide additional evidence that Kim-1 is a sensitive biomarker of the early stages of Cd-induced proximal tubule injury.
The American Journal of Pathology, 2005
The presence of macrophages in inflamed glomeruli of rat kidney correlates with proliferation and... more The presence of macrophages in inflamed glomeruli of rat kidney correlates with proliferation and apoptosis of resident glomerular mesangial cells. We assessed the contribution of inflammatory macrophages to progressive renal injury in murine crescentic glomerulonephritis (GN). Using a novel transgenic mouse (CD11b-DTR) in which tissue macrophages can be specifically and selectively ablated by minute injections of diphtheria toxin, we depleted renal inflammatory macrophages through days 15 and 20 of progressive crescentic GN. Macrophage depletion reduced the number of glomerular crescents, improved renal function, and reduced proteinuria. Morphometric analysis of renal tubules and interstitium revealed a marked attenuation of tubular injury that was associated with reduced proliferation and apoptosis of tubular cells. The population of interstitial myofibroblasts decreased after macrophage depletion and interstitial fibrosis also decreased. In the presence of macrophages, interstitial myofibroblasts exhibited increased levels of both proliferation and apoptosis, suggesting that macrophages act to support a population of renal myofibroblasts in a high turnover state and in matrix deposition. Finally, deletion of macrophages reduced CD4 T cells in the diseased kidney. This study demonstrates that macrophages are key effectors of disease progression in crescentic GN, acting to regulate parenchymal cell populations by modulating both cell proliferation and apoptosis.
Nature Communications, 2020
The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptiv... more The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can also lead to fibrosis and progressive kidney disease. There is currently limited knowledge about transcriptional regulators regulating these repair programs. Herein we establish the enhancer and super-enhancer landscape after AKI by ChIP-seq in uninjured and repairing kidneys on day two after ischemia reperfusion injury (IRI). We identify key transcription factors including HNF4A, GR, STAT3 and STAT5, which show specific binding at enhancer and super-enhancer sites, revealing enhancer dynamics and transcriptional changes during kidney repair. Loss of bromodomain-containing protein 4 function before IRI leads to impaired recovery after AKI and increased mortality. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data a...
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Papers by Joseph Bonventre