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David Basile, Ph.D.

Associate Professor

Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, MS 2063
Indianapolis, Indiana 46202-5120

E-mail: dpbasile @ iupui.edu
Phone: 317-278-1565
Facsimile: 317-274-3318

Education / Training

  • 1987, B.S., Marquette University, Milwaukee, Wisconsin
  • 1990, M.S. in Physiology, University of Illinois, Urbana, Illinois
  • 1994, Ph.D. in Physiology, University of Illinois, Urbana, Illinois
  • 1998, Postdoctoral Fellowship in Nephrology, Washington University, St. Louis, Missouri

   Research Biography Summary

 Personal Statemen

Work in my laboratory has been directed toward elucidating the pathophysiology of acute kidney injury and chronic kidney disease.  Since 2001, my lab has focused on studying the functional chronic consequences of acute kidney injury with particular questions related to the altered vasculature.   My laboratory can provide trainees with experiences in several areas of ongoing research as described below.

a)    Causes of CKD following AKI.   My laboratory is well-versed with the models and methodologies related to the establishment of renal injury, the measurements of CKD and fibrosis, evaluation of capillary structure and the isolation and culture of endothelial cells from kidney and other organs. We are also capable of whole animal physiological measurements including measurements of blood flow and blood pressure by telemetry and multiple molecular biological and imaging techniques geared at measuring gene and protein expression.  Recent studies in this area have focused on how renal injury alters the profile of lymphocytes with potential pro-inflammatory and renal hemodynamic consequences.

b)    Influences of mitochondrial adaptations on resistance to ischemic injury.  Work in collaboration with Dr. Bacallao in the Division of Nephrology have focused on how adaptations in the mitochondrial proteome may provide resistance to injury following renal ischemia reperfusion. This highly integrative and collaborative projects may involve investigation of experimental and genetic models of AKI resistance, methods to over express mitochondrial genes in kidney in vivo, investigation of mitochondrial responses using respiratory and microscopy methodologies, and evaluation of renal hemodynamic responses to mitochondrial manipulation,

c)     Investigation into renal revascularization strategies following injury.  In collaboration with Dr. Mervin Yoder in the Department of Pediatrics, we have successfully established long term cultures of renal derived endothelial cells from rats.  We have investigated the unique cellular properties of renal derived endothelial cells and demonstrated that these have impaired growth potential relative to other cultured endothelial cells with high percentage of progenitor ECFC.  We have conducted studies using ECFC as potential therapeutic treatments in the course of ischemia reperfusion injury. Our collaboration remains focused on the long term goal of re-establishing renal vascularization by using either ECFC based cell-therapy or determining ways to improve endogenous renal endothelial proliferative capacity. 

Contribution to Science

Bibliography http://www.ncbi.nlm.nih.gov/sites/myncbi/1jo48Y-vV59/bibliography/48073922/public/?sort=date&direction=ascending

1)    Acute kidney injury predisposes chronic kidney disease by incomplete repair of the renal microvasculature.

I began studying renal repair processes following acute kidney injury during the 1990s, during my post-doctoral training.  At that time, there was considerable research effort in the field focused on growth factors that may augment renal cell proliferation to hasten recovery.  Since proximal tubule cell proliferation represents only a small component of renal repair, I was compelled to examine the process of renal recovery by examining the degree to which other elements of renal structure and function are restored following an insult.  Using a model of renal ischemia/reperfusion, we examined renal structure at time points long after the after the re-establishment of serum creatinine and the re-establishment of proximal tubular morphology. Our studies demonstrated that recovery from renal I/R was associated with an early alteration in renal peritubular capillary density, a permanent alteration in urine concentrating ability, a late development of CKD.  Subsequent studies provided evidence that recovery from renal I/R was associated with hypoxia, serving as an important mediator of renal fibrosis. Since our hypothesis is that capillary loss represents a central event mediating the transition of AKI to CKD, studies sought to determine the expression profile of angiogenic factors.  We observed that a large number of anti-angiogenic factors were expressed post AKI, while the prominent pro-angiogenic growth factor, VEGF was inhibited by renal I/R.   Additional studies beginning around 2008 sought to evaluate the mechanisms of renal capillary loss. Our data suggested that VEGF administration preserves capillaries not via proliferation but by prevention of endothelial mesenchymal transition. We have hypothesized that a major deficit in recovery is due to the lack of impaired renal endothelial growth.  In collaboration with Dr. Merv Yoder, we have demonstrated that renal derived EC have low proliferative capacity relative to EC from other tissues, but the nature of this low growth potential has not yet been elucidated.

  • Basile DP, Donohoe D, Roethe K, and Osborn JL.  Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function.  Am J. Physiol. 281:F887-899, 2001.  PMID: 11592947
  • Basile DP, Donohoe DL, Roethe K, Mattson DL. Chronic renal hypoxia following ischemia/reperfusion injury: Effects of L-Arginine on hypoxia and secondary damage. Am J Physiol Renal Physiol.;284:F338-48. 2003PMID:12388385
  • Basile DP, Fredrich K, Chelladurai B, Leonard EC, Parrish AR. Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1 a novel VEGF inhibitor. Am J Physiol. 2008, 294: F928-36, PMID 18272597
  • Leonard, EC, Friedrich, JL and Basile, DP. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury, Am J. Physiol, 295:F1648-57, 2008.  PMC2604827
  • Basile DP, Fredrich K, Alausa M, Vio CP, Liang M, Rieder MR, Greene AS, Cowley AW Jr. Identification of persistently altered gene expression in the kidney after functional recovery from ischemic acute renal failure. Am J Physiol Renal Physiol 2005, 288:F953-61, PMID 15632414.
  • Spurgeon KR G., Donohoe DL, and Basile DP. Transforming growth factor-ß in acute renal failure: effects on cell proliferation, cellularity and vascularity after recovery from injury.  Am J Physiol Renal Physiol  288: F568-567, 2005. PMID:15536165|
  • Basile DP,  Fredrich K, Alausa M, Liang M,  Greene AS and Cowley, Jr AW. Identification of persistently altered gene expression in kidney following functional recovery from ischemic acute renal failure.  Am. J. Physiol, Renal Physiol: 288:953-963, 2005. PMID: 15632414
  • Basile, D. P.; Zeng, P.; Friedrich, J. L.; Leonard, E.; Yoder, M. C., Low proliferative potential and impaired angiogenesis of cultured rat kidney endothelial cells. Microcirculation 2012 19, 598-609. PMID 22612333, PMC3458172
  • Basile, D. and Yoder MC "Renal endothelial dysfunction in acute kidney ischemia reperfusion. (Review) Cardiovascular & Haematological Disorders-Drug Targets 14:3-14, PMID: 25088124 PMCID:PMC4215733
  • Basile, DP. and Yoder MC. Circulating and resident endothelial progenitor cells.(Review) Journal of Cellular Physiology Jan;229(1):10-6. doi: 10.1002/jcp.24423. 2014 PMID:23794280 PMC3908443
  • Basile DP,  Friedrich JL, Spahic J, Knipe N, Mang H, Leonard EC, Ashtiyani SC, Bacallao RL, Molitoris BA, and Sutton TA.  Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol: 300 F721-733, 2011.  PMID:21123492

 2)    Acute kidney injury induces salt sensitive hypertension and CKD: influence of altered immune and vascular control.

The observed rarefaction of renal capillaries in the renal medulla compelled us to examine whether recovery from AKI predisposed the development of salt-sensitivity.  In a series of studies beginning around 2005, we examined altered physiological responses in the kidney related to blood pressure regulation. We demonstrated that post AKI rats, when transferred to high salt diets became hypertensive and showed rapid progression of CKD.   This was due in part to altered renal sodium handling as evidence by  impaired sodium excretion function in pressure natriuresis studies.  Strategies to reverse capillary rarefaction by supplementing with VEGF activity, attenuated the development of salt sensitive chronic kidney disease.  In addition, we observed that AKI altered renal and non-renal vascular reactivity, particular to Ang II.  These responses were long-lived for up to several weeks following recovery from AKI and were attributable in part to increased local oxidant stress levels in renal or non-renal vasculature.  Finally, we demonstrated that immune suppression markedly attenuates the development of salt sensitivity following recovery from AKI.  Furthermore, we demonstrated that elevated immune cells are present in both injured and contralateral kidneys following acute unilateral IR and that contralateral kidney can mediate salt sensitivity.  Recent studies have demonstrated that CD4+-IL17+ cells represent the dominant T cell induced by salt diet, and are hypothesized to play a central role in the development of salt sensitivity.  

  • Spurgeon-Pechman, KR, Mattson DL and Basile DP, Recovery from ischemic acute renal failure predisposes hypertension and secondary renal disease in response to elevated sodium intake Am. J. Physiol Renal Physiol 293: F269-78, 2007.  PMID:  17507599
  • Basile DP, Donohoe DL, Phillips SAG, and Frisbee JC.  Enhanced skeletal muscle arteriolar reactivity to ANG II after recovery from ischemic acute renal failure.  Am J Physiol Regul Integr Comp Physiol 289: R1770-R1776, 2005.
  • Pechman, KR, DeMiguel D, Lund H, Leonard EC, Basile DP, and Mattson DL.  Recovery from renal ischemia reperfusion injury is associated with altered renal hemodynamics, blunted pressure natriuresis and sodium sensitive hypertension. Am J. Physiol. Regul Integr 297(5): R1358 - R1363, 2009.  PMCID: PMC2777774
  • Basile, DP, Leonard, EC, Beal, AG, Schleuter, D & Friedrich, JL: Persistent oxidative stress following renal ischemia reperfusion injury increases Ang II hemodynamic and fibrotic activity. American Journal of Physiology - Renal Physiology, 302:F1494-502, 2012 PMID 22442209, 2012.|Spurgeon Pechman, KR,   Basile DP, Lund, H, and DL Mattson.  Immune suppression blocks sodium sensitive hypertension following recovery from acute renal failure.  Am J. Physiol. Regul Integr. 294(4): R1234-R1239, 2008.  PMID:18256138.
  • Basile, DP, Leonard, EC, Tonade, D, Friedrich, JL & Goenka, S: Distinct effects on long-term function of injured and contralateral kidneys following unilateral renal ischemia-reperfusion. American Journal of Physiology - Renal Physiology, 302: F625-F635, 2012. PMID 22114210*Mehrotra, P, Patel JBU, Ivancic CMU, Collet JAF and Basile DP.  Th-17 cell activation in response to high salt following AKI is associated with progressive fibrosis and attenuated by AT-1R antagonism. Kidney International, In Press, 2015.

 3)    Acute kidney injury is influenced by genetic background.

Studies beginning around 2003 in collaboration with Dr. Scott Van Why sought to determine whether information regarding cellular injury or protection could be gathered from different strains of rats. The rational for this approach was based on the promise to study the contribution of different biochemical pathways with genomic approaches if distinct strain differences could be found.  Interestingly, we observed the Brown Norway rat was remarkably resistant to injury and manifested an up-regulation of stress response proteins.  Additional studies using an entire panel of consomic rats with chromosomes introgressed from injury resistant BN into the background of injury prone DahlS rats suggest that the response is the cumulative result of multiple genes on several different chromosomes.  These data have served as an important feature for a collaborative VA grant with Dr. Bacallao on mitochondrial resistance of AKI which is influenced by genetic background.

  • Basile DP, Donohoe D, Cao X, and Van Why SK.  Resistance to ischemic acute renal failure in the Brown Norway rat: A new model to study cytoprotection Kidney Intl 65:2201-2211, 2004.
  • Basile, DP.; Dwinell, M.; Wang, S.; Shames, B. D.; Donohoe, D.; Chen, S.; Sreedharan, R.; Van Why, S., Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats. Kidney International 2013,83, 242-250. PMID 23235564 PMC3561482

Research

Work in our laboratory is directed toward elucidating the pathophysiology of acute kidney injury (AKI) and its relationship to the development of chronic kidney disease (CKD). The laboratory uses rodent models of AKI induced by ischemia/reperfusion. Several topics related to the pathophysiology of AKI are being pursued.

A primary interest in the laboratory relates to the long-term sequelae of acute kidney injury. Work from our laboratory has shown that acute renal ischemia, which typically induces a reversible tubular injury, chronically reduces the density of renal blood vessels and increases the deposition of interstitial fibroblasts (Figure 1).  The cellular basis for the loss of renal capillaries is unknown, but may be due a combination of endothelial cell transformation (Figure 2) and/or a lack of appropriate growth cues and resident cellular  regenerative potential.

Renal blood vessel loss is thought to promote hypoxia in the kidney and fuel fibrosis leading to progressive chronic kidney disease (CKD).  The preservation of blood vessels following acute kidney injury protects the kidney from long term inflammatory destruction (Figure 3).  Alterations in renal sodium handling also occur and predispose the development of hypertension. Our long term goals are to how these structural alterations affect renal function and predispose secondary disease.

The laboratory utilizes a variety of whole-animal physiological approaches, transgenic and consomic animal models, molecular, genetic, biochemical and histochemical strategies to investigate the genesis of kidney disease. The laboratory has active collaborations with individuals in the IUSM Department of Pediatrics, Immunology and the Division of Nephrology which help to provide an integrative perspective on the etiology of disease and also to offer a broad-based training opportunity for graduate students.

Currently, projects in the laboratory can be grouped into 3 broad categories.

  1. Determination of the mechanisms of renal capillary dropout which focus on issues of impaired endothelial progenitor activity within the kidney and cellular basis for the resistance to vascular repair responses.

  2. Determination of the immune modulation of long term kidney function following acute injury. Current focus includes an evaluation of T lymphocyte differentiation as a function of injury and dietary salt, and the consequential activation of antigen presenting cells which fuel progressive kidney disease.  Additional studies seek to understand how T lymphocyte activity may modulate renal hemodynamic activity and promote hypertension and chronic kidney disease.

  3. Evaluation of genetic and experimental models of resistance to acute kidney injury with the goal of evaluating mitochondrial activity as the basis for the initiation of AKI.  Alterations in gene expression associated with resistance to ischemic injury may provide for the identification of candidate genes with protective activity. The translation of such genes in vivo provides an opportunity to study the pathophysiology of acute kidney injury.

 

Selected Publications

1.  Corridon PR, Rhodes GJ, Leonard E, Basile DP, Gattone, VH, Bacallao RL, and Atkinson. SJ. A method to facilitate and monitor expression of exogenous genes in the rat kidney using plasmid and viral vectors. American Journal of Physiology-Renal Physiology 304: F1217-1229, 2013.

2.  Basile DP, Dwinell M, Wang S, Shames BD, Donohoe D, Chen S, Sreedharan R, and Van Why S. Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats. Kidney International 83: 242-250, 2013.

3.  Basile DP, Leonard EC, Tonade D, Friedrich JL, and Goenka S. Distinct effects on long-term function of injured and contralateral kidneys following unilateral renal ischemia-reperfusion. American Journal of Physiology - Renal Physiology 302: F625-F635, 2012.

4.  Basile DP, Leonard EC, Beal AG, Schleuter D, and Friedrich JL. Persistent oxidative stress following renal ischemia reperfusion injury increases Ang II hemodynamic and fibrotic activity. American Journal of Physiology - Renal Physiology 302: 2012.

5.  Basile DP, Zeng P, Friedrich JL, Leonard E, and Yoder MC. Low proliferative potential and impaired angiogenesis of cultured rat kidney endothelial cells. Microcirculation 19: 598-609, 2012

6.  Basile DP, Friedrich JL, Spahic J, Knipe NL, Mang HE, Leonard EC, Ashtiyani SC, Bacallao RL, Molitoris BA, and Sutton TA. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. American Journal of Physiology - Renal Physiology 300: F721-733, 2011.

7.  Phillips SA, Pechman KR, Leonard EC, Friedrich JL, Bian J-T, Beal AG, and Basile DP. Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries. Am J Physiol Regul Integr Comp Physiol 298: R1682-1691, 2010.

8.  Pechman KR, De Miguel C, Lund H, Leonard EC, Basile DP, and Mattson DL. Recovery from renal ischemia-reperfusion injury is associated with altered renal hemodynamics, blunted pressure natriuresis, and sodium-sensitive hypertension. Am J Physiol Regul Integr Comp Physiol 297: R1358-1363, 2009.

9. Jung J, Basile DP, and Pratt JH. Sodium Reabsorption in the Thick Ascending Limb in Relation to Blood Pressure. Hypertension 57: 873-879, 2011.

10. Basile DP, Fredrich K, Chelladurai B, Leonard EC, and Parrish AR. Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am J Physiol Renal Physiol 294: 2008

11. Leonard EC, Friderich J, and Basile DP. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol-Renal Physiol 295: F1648-1657, 2008.

12.  Basile DP, Donohoe DL, Roethe K, and Mattson DL. Chronic renal hypoxia following ischemia/reperfusion injury: Effects of L-Arginine on hypoxia and secondary damage. Am J Physiol Renal Physiol 284: F338-348, 2003. 

13.  Basile DP, Donohoe DL, Roethe K, and Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. American Journal of Physiology 281: F887-F899, 2001.

 

 

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Updated: 04/08/2016

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