IU Indianapolis ScholarWorks :: Browsing by Author "Basile, David P."

Browsing by Author "Basile, David P."

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Anti-angiogenic activity of kidney derived endothelial cells
(Office of the Vice Chancellor for Research, 2013-04-05) Basile, David P.; Mallet, Coleen; Yoder, Mervin C.
The identification of novel endogenous mediators of angiogenic/vasculogenic processes may provide for novel therapeutic targets to modulate blood vessel growth in disease states, such as cardiovascular disease or cancer. Studies in our lab have shown that blood vessels in kidney have little endogenous regenerative capacity. Kidney derived microvascular endothelial cells (KEC) were isolated from rat kidney or from transgenic mice bearing the temperature sensitive SV40 mutant (and subsequently grown at non-permissive temperature, 37oC). Both rat and mouse KECs manifested significantly reduced growth rates when compared with several commonly used EC lines (rat pulmonary EC, HUVEC and human cord blood colony forming ECs). In 2D matrigel assays, all commonly used ECs faithfully formed characteristic branching structures; while all KECs failed to form stabile branching structures. Time-course analysis of branching activity demonstrated that KEC initially formed primitive branching nodes within 3 hours of culture, but these structures regressed such that no branched structures were observed between 6-12 hours. Co-culture of KECs with any branching competent EC impaired branching dose dependently. When co-cultured with ECFC, labeled KECs incorporated into primitive ECFC branches within the first 3 hours of plating. However, when compared with ECFC branches, ECFC-KEC mixed branches showed a more rapid regression of the branched structures between 12-24 hrs. Interestingly, conditioned media from KEC did not affect branching of competent ECFC. Taken together, these data indicate that KEC have anti-angiogenic activity that may destabilize ECs during angiogenesis. The anti-angiogenic activity requires cell-cell contact, suggesting the possible presence of an angio-inhibitory molecule on the cell surface of KECs. Current and future studies seek to generate additional KEC lines, and will determine if KEC cell fractions mediate the anti-angiogenic effect. In addition, we will seek to determine if KECs mitigate progression of angiogenic dependent tumor formation in vivo.
Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury
(American Society for Clinical Investigation, 2019-11-01) Mehrotra, Purvi; Sturek, Michael; Neyra, Javier A.; Basile, David P.; Anatomy and Cell Biology, School of Medicine
We hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1+ CD4 T cells and IL-17 expression was restricted to Orai1+ cells. When kidney CD4+ cells of post-acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10-7 M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM58483/BTP2 (1 mg/kg) attenuated IL-17+ cell activation, inflammation, and severity of AKI following either I/R or intramuscular glycerol injection. Rats treated with high-salt diet (5-9 weeks after I/R) manifested progressive disease indicated by enhanced inflammation, fibrosis, and impaired renal function. These responses were significantly attenuated by YM58483/BTP2. In peripheral blood of critically ill patients, Orai1+ cells were significantly elevated by approximately 10-fold and Th17 cells were elevated by approximately 4-fold in AKI versus non-AKI patients. Further, in vitro stimulation of CD4+ cells from AKI patients increased IL-17, which was blocked by SOCE inhibitors. These data suggest that Orai1 SOCE is a potential therapeutic target in AKI and CKD progression.
The case for capillary rarefaction in the AKI to CKD progression: insights from multiple injury models
(American Physiological Society, 2019-11) Basile, David P.; Anatomy and Cell Biology, School of Medicine
Contribution of Th17 cells to tissue injury in hypertension
(Wolters Kluwer, 2021) Basile, David P.; Abais-Battad, Justine M.; Mattson, David L.; Anatomy, Cell Biology and Physiology, School of Medicine
Purpose of review: Hypertension has been demonstrated to be a chief contributor to morbidity and mortality throughout the world. Although the cause of hypertension is multifactorial, emerging evidence, obtained in experimental studies, as well as observational studies in humans, points to the role of inflammation and immunity. Many aspects of immune function have now been implicated in hypertension and end-organ injury; this review will focus upon the recently-described role of Th17 cells in this pathophysiological response. Recent findings: Studies in animal models and human genetic studies point to a role in the adaptive immune system as playing a contributory role in hypertension and renal tissue damage. Th17 cells, which produce the cytokine IL17, are strongly pro-inflammatory cells, which may contribute to tissue damage if expressed in chronic disease conditions. The activity of these cells may be enhanced by physiological factors associated with hypertension such as dietary salt or Ang II. This activity may culminate in the increased sodium retaining activity and exacerbation of inflammation and renal fibrosis via multiple cellular mechanisms. Summary: Th17 cells are a distinct component of the adaptive immune system that may strongly enhance pathways leading to increased sodium reabsorption, elevated vascular tone and end-organ damage. Moreover, this pathway may lend itself towards specific targeting for treatment of kidney disease and hypertension.
Crystals or His(stones): Rethinking AKI in Tumor Lysis Syndrome
(Wolters Kluwer, 2022) Basile, David P.; Anatomy, Cell Biology and Physiology, School of Medicine
Damaging effects of cigarette smoke on organs and stem/progenitor cells and the restorative potential of cell therapy
(2017-06-23) Barwinska, Daria; March, Keith L.; Basile, David P.; Broxmeyer, Hal; Clauss, Matthias; Traktuev, Dmitry O.
Cigarette smoking (CS) continues to be a significant modifiable factor contributing to a variety of diseases including cardiovascular, pulmonary and renal pathologies. It was suggested that smoking have detrimental effect of the body’s progenitor cells of bone marrow and peripheral organs. Since the concept of cell therapy that utilizes adipose stem/stromal cells (ASC) is gaining momentum it becomes critical to assess the therapeutic activities of the progenitors isolated from smokers. This study has revealed that CS negatively impacts the vasculogenic potential of ASC, in vitro, as well as weakening their therapeutic activity in vivo when tested in mouse model of hindlimb ischemia. We hypothesized that the decrease in vasculogenic activity of ASC is attributed to a higher level of expression of an angiostatic factor Activin A by ASC from CS donors. These findings clearly suggest that smokers should be evaluated for potential exclusion from early clinical trials of autologous cell therapies, or assessed as a separate cohort. The donor’s health status should be considered when choosing between autologous vs allogeneic cell therapies. We then examined the effect of CS on development of kidney pathology in mice. CS exposure led to decrease in kidney weights, capillary rarefaction, and cortical blood perfusion, and in parallel led to increase in kidney fibrosis and iron deposition. Interestingly, infusion of healthy ASC to the mice following CSexposure reversed CS-induced damages. This strongly support the notion that ASC-based therapy may provide rejuvenation effect. In the other subset of studies, we hypothesized that CS-induced lung emphysematous changes are preceded by suppression of bone marrow (BM) hematopoietic progenitor cells (HPC). We have revealed that intermittent BM mobilization with AMD3100 may mitigate the CS-induced myelo-suppression and deterioration of lung function and morphology. We observed that treatment of mice with AMD3100, while exposed to CS, preserves HPC at the levels of healthy control mice. Furthermore, AMD3100 treatment preserved lung parenchyma from pathological changes. These data suggest that while CS has a myelo-suppressive effect, administration of AMD3100 preserved BM-HPC and ameliorated lung damage.
Effect of renal shock wave lithotripsy on the development of metabolic syndrome in a juvenile swine model: a pilot study
(Elsevier, 2015-04) Handa, Rajash K.; Liu, Ziyue; Connors, Bret A.; Alloosh, Mouhamad; Basile, David P.; Tune, Johnathan D.; Sturek, Michael; Evan, Andrew P.; Lingeman, James E.; Department of Anatomy & Cell Biology, IU School of Medicine
PURPOSE: We performed a pilot study to assess whether renal shock wave lithotripsy influences metabolic syndrome onset and severity. MATERIALS AND METHODS: Three-month-old juvenile female Ossabaw miniature pigs were treated with shock wave lithotripsy (2,000 shock waves at 24 kV with 120 shock waves per minute in 2) or sham shock wave lithotripsy (no shock waves in 2). Shock waves were targeted to the upper pole of the left kidney to model treatment that would also expose the pancreatic tail to shock waves. Pigs were then instrumented to directly measure arterial blood pressure via an implanted radiotelemetry device. They later received a hypercaloric atherogenic diet for about 7 months. Metabolic syndrome development was assessed by the intravenous glucose tolerance test. RESULTS: Metabolic syndrome progression and severity were similar in the sham treated and lithotripsy groups. The only exception arterial blood pressure, which remained relatively constant in sham treated pigs but began to increase at about 2 months towards hypertensive levels in lithotripsy treated pigs. Metabolic data on the 2 groups were pooled to provide a more complete assessment of metabolic syndrome development and progression in this juvenile pig model. The intravenous glucose tolerance test revealed substantial insulin resistance with impaired glucose tolerance within 2 months on the hypercaloric atherogenic diet with signs of further metabolic impairment at 7 months. CONCLUSIONS: These preliminary results suggest that renal shock wave lithotripsy is not a risk factor for worsening glucose tolerance or diabetes mellitus onset. However, it appears to be a risk factor for early onset hypertension in metabolic syndrome.
Endothelial colony-forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury
(American Physiological Society, 2017-05-01) Collett, Jason A.; Mehrotra, Purvi; Crone, Allison; Shelley, W. Christopher; Yoder, Mervin C.; Basile, David P.; Cellular and Integrative Physiology, School of Medicine
Damage to endothelial cells contributes to acute kidney injury (AKI) by leading to impaired perfusion. Endothelial colony-forming cells (ECFC) are endothelial precursor cells with high proliferative capacity, pro-angiogenic activity, and in vivo vessel forming potential. We hypothesized that ECFC may ameliorate the degree of AKI and/or promote repair of the renal vasculature following ischemia-reperfusion (I/R). Rat pulmonary microvascular endothelial cells (PMVEC) with high proliferative potential were compared with pulmonary artery endothelial cells (PAEC) with low proliferative potential in rats subjected to renal I/R. PMVEC administration reduced renal injury and hastened recovery as indicated by serum creatinine and tubular injury scores, while PAEC did not. Vehicle-treated control animals showed consistent reductions in renal medullary blood flow (MBF) within 2 h of reperfusion, while PMVEC protected against loss in MBF as measured by laser Doppler. Interestingly, PMVEC mediated protection occurred in the absence of homing to the kidney. Conditioned medium (CM) from human cultured cord blood ECFC also conveyed beneficial effects against I/R injury and loss of MBF. Moreover, ECFC-CM significantly reduced the expression of ICAM-1 and decreased the number of differentiated lymphocytes typically recruited into the kidney following renal ischemia. Taken together, these data suggest that ECFC secrete factors that preserve renal function post ischemia, in part, by preserving microvascular function.
Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury
(Wiley, 2017) Basile, David P.; Collett, Jason A.; Yoder, Mervin C.; Department of Cellular & Integrative Physiology, IU School of Medicine
Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as ‘endothelial progenitor’ that may mediate vascular repair such as pro-angiogenic cells and endothelial colony-forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre-clinical studies.
Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection
(American Society of Nephrology, 2018-04) Kolb, Alexander L.; Corridon, Peter R.; Zhang, Shijun; Xu, Weimin; Witzmann, Frank A.; Collett, Jason A.; Rhodes, George J.; Winfree, Seth; Bready, Devin; Pfeffenberger, Zechariah J.; Pomerantz, Jeremy M.; Hato, Takashi; Nagami, Glenn T.; Molitoris, Bruce A.; Basile, David P.; Atkinson, Simon J.; Bacallao, Robert L.; Biology, School of Science
Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. A substantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes in mitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP+-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of Idh2 gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of IDH2 before injury attenuated the injury-induced rise in serum creatinine (P<0.05) observed in controls and increased the mitochondria membrane potential (P<0.05), maximal respiratory capacity (P<0.05), and intracellular ATP levels (P<0.05) above those in controls. This communication shows that gene delivery of Idh2 can confer organ-wide protection against subsequent ischemia-reperfusion injury and mimics ischemic preconditioning.

Browsing by Author "Basile, David P."

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