While the clinical relevance of proteinuria, and especially albuminuria, has been well documented the quantitative mechanistic contribution or role of different barrier components to albuminuria remains an area of considerable excitement and debate. Recent data from several laboratories utilizing different scientific approaches have delineated a potential role of proximal tubules in albumin reabsorption and reclamation as another important determinant of the urinary barrier to albuminuria. Therefore, the present application proposes to dissect apart and quantify glomerular and proximal tubule contributions to albuminuria under physiologic and disease conditions in a longitudinal fashion in the same rats. Structural, functional and mechanistic observations will be interrelated to advance our present understanding of this clinically important phenomenon. Our Overall Hypothesis is that both glomerular permeability and proximal tubule cells play fundamental, physiologic, synergistic, interactive and inducible roles to try and maintain the physiological state and minimize albuminuria. We further hypothesize that acute or chronic alterations in glomerular albumin permeability or in proximal tubule albumin reclamation can directly affect albuminuria. To directly evaluate this hypothesis we have developed the necessary techniques, approaches and animal models to dissect, quantify, understand and interrelate the role of acute and chronic changes in glomerular permeability and proximal tubular cell reabsorption and transcytosis of filtered albumin.

Public Health Relevance

While the importance of protein (albumin) in the urine in disease progression is known, the key mechanism(s) mediating the presence of and toxic effects of albumin still remain to be determined. The proposed studies will lead to an enhanced mechanistic understanding of the cellular processes involved in albuminuria, their role in disease processes resulting in proteinuria thereby leading the way toward development of possible novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK091623-01A1
Application #
8235552
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2011-09-30
Project End
2016-07-31
Budget Start
2011-09-30
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$337,306
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
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
Dunn, Kenneth W; Sutton, Timothy A; Sandoval, Ruben M (2018) Live-Animal Imaging of Renal Function by Multiphoton Microscopy. Curr Protoc Cytom 83:12.9.1-12.9.25
Endres, Bradley T; Sandoval, Ruben M; Rhodes, George J et al. (2017) Intravital imaging of the kidney in a rat model of salt-sensitive hypertension. Am J Physiol Renal Physiol 313:F163-F173
Sandoval, Ruben M; Molitoris, Bruce A (2017) Intravital multiphoton microscopy as a tool for studying renal physiology and pathophysiology. Methods 128:20-32
Rhodes, George J (2017) Surgical preparation of rats and mice for intravital microscopic imaging of abdominal organs. Methods 128:129-138
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
Hato, Takashi; Winfree, Seth; Day, Richard et al. (2017) Two-Photon Intravital Fluorescence Lifetime Imaging of the Kidney Reveals Cell-Type Specific Metabolic Signatures. J Am Soc Nephrol 28:2420-2430
Wagner, Mark C; Campos-Bilderback, Silvia B; Chowdhury, Mahboob et al. (2016) Proximal Tubules Have the Capacity to Regulate Uptake of Albumin. J Am Soc Nephrol 27:482-94
Molitoris, Bruce A; Reilly, Erinn S (2016) Quantifying Glomerular Filtration Rates in Acute Kidney Injury: A Requirement for Translational Success. Semin Nephrol 36:31-41
Wagner, Mark C; Myslinski, Jered; Pratap, Shiv et al. (2016) Mechanism of increased clearance of glycated albumin by proximal tubule cells. Am J Physiol Renal Physiol 310:F1089-102

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