Acute renal failure is thought to be largely reversible if the patient survives the initial insult. Patients following recovery from ARF may be susceptable to progressive renal disease, although this is not commonly observed. In contrast, ischemic injury in a transplanted kidney can result in delayed graft function (DGF) which is a clearly a risk factor for long-term graft demise. To understand more clearly the nature of the relationship between acute renal injuries and progressive nephropathies, we have studied rats following recovery from either unilateral or bilateral ischemia/reperfusion injury and showed that there is a permanent alteration in the structure of renal per/tubular capillaries. We hypothesize that a reduction in renal per/tubular capillaries alters renal function and predisposes the development of chronic renal disease. This application is directed toward elucidating the physiological and pathophysiological implications of acute injuries and to decipher possible mechanims by which renal per/tubular capillaries are lost following acute insults.
In specific aim #1, we will explore further the ramification of acute injury on long-term renal function. In this aim, we will investigate alterations in renal pO2 using BOLD MRI. In addition, we will determine if nephrotoxic (e.g., cyclosporine) injury can affect per/tubular capillaries in a fashion similar to that observed with I/R injury. We will also determine if post-ischemic recovered animals have are affected in their renal Na handling abilities and develop salt-sensitive hypertension. We will also determine whether potential intervential therapies (ACE/, VEGF) affect I/R induced changes in renal capillary density, renal hypoxia and/or the progression of chronic renal disease. Finally, we will analyze gene expression patterns in recovered kidneys to gain insight into the potential mechanisms of chronic renal failure following acute injury.
In Specific Aim #2, we will perform experiments geared toward understanding the mechanims of blood vessel loss following injury. In this aim, we will characterize the expression of several angiogenic and antiangiogenic molecules in response to I/R injury. The second aspect of this aim is geared toward deciphering the role and regulation of angiostatin using different strains of knockout mice or newly acquired metalloprotease inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063114-05
Application #
7103605
Study Section
General Medicine B Study Section (GMB)
Program Officer
Wilder, Elizabeth L
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2008-04-30
Support Year
5
Fiscal Year
2006
Total Cost
$252,167
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Kolb, Alexander L; Corridon, Peter R; Zhang, Shijun et al. (2018) Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection. J Am Soc Nephrol 29:1154-1164
Mehrotra, Purvi; Collett, Jason A; Gunst, Susan J et al. (2018) Th17 cells contribute to pulmonary fibrosis and inflammation during chronic kidney disease progression after acute ischemia. Am J Physiol Regul Integr Comp Physiol 314:R265-R273
Basile, D P; Collett, J A; Yoder, M C (2018) Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury. Acta Physiol (Oxf) 222:
Collett, Jason A; Mehrotra, Purvi; Crone, Allison et al. (2017) Endothelial colony-forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury. Am J Physiol Renal Physiol 312:F897-F907
Collett, Jason A; Traktuev, Dmitry O; Mehrotra, Purvi et al. (2017) Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury. J Cell Mol Med 21:1420-1430
Mehrotra, Purvi; Collett, Jason A; McKinney, Seth D et al. (2017) IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats. Am J Physiol Renal Physiol 312:F385-F397
Collett, Jason A; Corridon, Peter R; Mehrotra, Purvi et al. (2017) Hydrodynamic Isotonic Fluid Delivery Ameliorates Moderate-to-Severe Ischemia-Reperfusion Injury in Rat Kidneys. J Am Soc Nephrol 28:2081-2092
Basile, David P; Mehrotra, Purvi (2017) Surprising Enhancement of Fibrosis by Tubule-Specific Deletion of the TGF-? Receptor: A New Twist on an Old Paradigm. J Am Soc Nephrol 28:3427-3429
de Bragança, Ana C; Volpini, Rildo A; Mehrotra, Purvi et al. (2016) Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury. Physiol Rep 4:
Basile, David P; Bonventre, Joseph V; Mehta, Ravindra et al. (2016) Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments. J Am Soc Nephrol 27:687-97

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