A5002644615- Acute Kidney Injury Research
- Metabolism and Genetic Disorders
- Chronic Kidney Disease and Diabetes
- Renal and related cancers
- Cardiac Ischemia and Reperfusion
- Peroxisome Proliferator-Activated Receptors
- Cardiac Arrest and Resuscitation
- Pancreatic function and diabetes
- Renal Diseases and Glomerulopathies
- Renal cell carcinoma treatment
- Eicosanoids and Hypertension Pharmacology
- Advanced Glycation End Products research
- Cancer, Hypoxia, and Metabolism
- Phagocytosis and Immune Regulation
- MicroRNA in disease regulation
- Circular RNAs in diseases
- Pregnancy and preeclampsia studies
- Biochemical Acid Research Studies
- Marine Ecology and Invasive Species
- Heme Oxygenase-1 and Carbon Monoxide
- Pregnancy and Medication Impact
- Diet and metabolism studies
- Tissue Engineering and Regenerative Medicine
- Metabolism, Diabetes, and Cancer
- Retinoids in leukemia and cellular processes
University of Pittsburgh
2019-2025
Children's Hospital of Pittsburgh
2019-2024
University of Pittsburgh Medical Center
2019-2023
Vanderbilt University Medical Center
2013-2015
Vanderbilt University
2015
Kyoto University
2004-2006
At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought identify candidate compounds that recovery AKI by screening for small molecules increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from this screen was the histone deacetylase inhibitor methyl-4-(phenylthio)butanoate, which subsequently administered larvae and mice 24-48 hours inducing In zebrafish,...
Significance Statement Proximal tubular epithelial cells, a primary site of injury in AKI, are rich mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Deletion Sirtuin 5 ( Sirt5 ) reverses posttranslational lysine acylation several enzymes involved The authors demonstrate mice lacking had significantly improved kidney function less tissue damage following either ischemia-induced or cisplatin-induced AKI compared with wild-type mice. These differences...
Vascularization plays a critical role in organ maturation and cell type development. Drug discovery, mimicry, ultimately transplantation hinge on achieving robust vascularization of vitro engineered organs. Here, focusing human kidney organoids, we overcame this hurdle by combining induced pluripotent stem (iPSC) line containing an inducible ETS translocation variant 2 (ETV2) (a transcription factor playing endothelial development) that directs differentiation vitro, with non-transgenic iPSC...
The renal tubular epithelial cells (RTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids the preferred energy source for RTECs via acid oxidation (FAO), FAO-mediated H2O2 production in mitochondria has been shown be a major of oxidative stress. We have previously that mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes key step FAO, directly produces vitro. Further, we showed LCAD becomes hyposuccinylated during AKI. Here,...
Phenylthiobutanoic acids (PTBAs) are a new class of histone deacetylase (HDAC) inhibitors that accelerate recovery and reduce postinjury fibrosis after ischemia-reperfusion-induced acute kidney injury. However, unlike the more common scenario in which patients present with protracted less clearly defined onset renal injury, this model injury gives rise to begins resolve over short period time. In these studies, we show for first time treatment PTBA analog methyl-4-(phenylthio)butanoate...
Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation this pathway what role it regulating repair after AKI. In these studies, we show that RA signaling activated mouse zebrafish responses limit extent promote normal repair. These effects were mediated through a novel mechanism by which coordinated dynamic equilibrium inflammatory M1 spectrum versus alternatively M2 macrophages. Our data suggest locally...
The aged population is currently at its highest level in human history and expected to increase further the coming years. In humans, aging accompanied by impaired angiogenesis, diminished blood flow altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of can be a suitable target for therapeutic intervention. Here we identify cell surface receptor CD47 as novel age-sensitive driver vascular metabolic dysfunction. With natural process, ligand...
Significance Statement Regulation of endothelial cells is important in many biologic processes, including development, organ function, and disease. The kidney vasculature highly sensitive to hypoxic injury has a limited capacity for repair. AKI as result decreased blood flow common, there are no current therapies. MicroRNAs small noncoding RNAs that inhibit expression target genes. Endothelial-derived miR-17∼92 cluster microRNAs critical function repair during mice. Furthermore,...
Significance Statement In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC not only affordable and easy administer but also effective. These encouraging findings suggest could potentially...
Clear cell renal carcinoma (ccRCC) is the most common kidney cancer and often caused by mutations in oxygen-sensing machinery of epithelial cells. Due to its pseudo-hypoxic state, ccRCC recruits extensive vasculature other stromal components. Conventional culture methods provide poor representation types primary cultures ccRCC, we hypothesized that mimicking extracellular environment tumor would promote growth both We employed proteomics identify components matrix (ECM) found contrast...
No therapies have been shown to accelerate recovery or prevent fibrosis after acute kidney injury (AKI). In part, this is because most therapeutic candidates be given at the time of and diagnosis AKI usually made too late for drugs efficacious. Strategies enhance post-AKI repair represent an attractive approach address this. Using a phenotypic screen in zebrafish, we identified 4-(phenylthio)butanoic acid (PTBA), which promotes proliferation embryonic progenitor cells (EKPCs), PTBA methyl...
Succinylation is an understudied posttranslational modification that has been shown to increase peroxisomal activity. Furthermore, increased activity reduce oxidative stress and protect proximal tubules after acute kidney injury. Analysis of mass spectrometry succinylomic proteomic data reveals a novel role for Parkinson’s related Park7 in mediating Nrf2 antioxidant response This protection pathway provides new insights injury prevention development therapeutics.
Cardiac arrest (CA) causes high mortality due to multi-system organ damage attributable ischemia-reperfusion injury. Recent work in our group found that among diabetic patients who experienced cardiac arrest, those taking metformin had less evidence of and renal after when compared not metformin. Based on these observations, we hypothesized metformin's protective effects the heart were mediated by AMPK signaling, signaling could be targeted as a therapeutic strategy following resuscitation...
Acute kidney injury (AKI) remains an important source of progressive chronic injury. Loss renal blood flow with subsequent restoration, termed ischemia reperfusion (IR), is a common cause AKI. The cell surface receptor signal regulatory protein α (SIRP-α) expressed on macrophages and limits inflammation phagocytosis. SIRP-α has recently been found to have wider cell-based expression play role in IR. We explored this genetic model deficient signaling. Mice lacking cytoplasmic signaling...
Aim Mouse models of sudden cardiac arrest are limited by challenges with surgical technique and obtaining reliable venous access. To overcome this limitation, we sought to develop a simplified method in the mouse that uses ultrasound-guided injection potassium chloride directly into heart. Methods Potassium was delivered left ventricular cavity under ultrasound guidance intubated mice, resulting immediate asystole. Mice were resuscitated epinephrine manual chest compressions evaluated for...
Prenatal hypoxia is a gestational stressor that can result in developmental abnormalities or physiological reprogramming, and often decreases cellular capacity against secondary stress. When developing fetus exposed to hypoxia, blood flow preferentially redirected vital organs including the brain heart over other kidney. Hypoxia-induced injury lead structural malformations kidney; however, even absence of lesions, physiologically reprogram kidney leading decreased function increased...
ABSTRACT Proximal tubular epithelial cells (PTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids the preferred energy source for PTECs via acid oxidation (FAO), FAO-mediated H 2 O production in mitochondria has been shown be a major of oxidative stress. We have previously that mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes key step FAO, directly produces vitro . Further we established loss lysine deacylase, Sirtuin 5 (...
Abstract Aim Mouse models of sudden cardiac arrest are limited by challenges with surgical technique and reliable venous access. To overcome this limitation, we sought to develop a simplified method in the mouse that uses ultrasound-guided injection potassium chloride directly into heart. Methods Potassium was delivered left ventricular cavity under ultrasound guidance intubated mice, resulting immediate asystole. Mice were resuscitated epinephrine manual chest compressions evaluated for...