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.
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.
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