Kidney cell function requires the maintenance of polarized plasma membrane domains with distinct protein and lipid compositions, and defects in proper targeting of proteins results in disease. Despite the critical role of cell polarity in maintaining kidney function, we know little about the mechanisms that selectively guide proteins to the apical and basolateral cell surfaces. Our long term goal is to understand how proteins are segregated and targeted to the apical surface of kidney cells with the objective of manipulating protein sorting to treat disease. Apical sorting signals are diverse and multiple biosynthetic routes exist to the apical plasma membrane. Here we propose a unifying model for apical protein sorting in which cargo clustering within sorting compartments provides the avidity necessary to recruit membrane and cytoplasmic proteins required for surface delivery. We will test this model using a protein with an essential role in kidney function that is targeted to the apical surface in a glycan dependent manner. Our proposed studies utilize cutting edge biophysical, biochemical, and proteomic approaches and take full advantage of the unique facilities and broad expertise in renal epithelial cell biology at the University of Pittsburgh. Ths work will significantly enhance our understanding of how apical sorting and polarity are maintained in the kidney and illuminate new strategies to manipulate protein traffic for therapeutic advantage.

Public Health Relevance

The primary function of the kidney is the reabsorption of water, ions, and metabolites from the forming urine to the bloodstream. The surfaces of kidney cells are subdivided into different domains that face the urine and bloodstream and that contain distinct proteins and lipids. This asymmetric distribution of surface components is essential for proper kidney function, and defects in protein targeting to these surface domains cause kidney disease. Our long term goal is to understand how kidney cells generate and maintain these distinct surface domains. The results of our research will provide critical basic information that can be applied to the design of potential therapies to combat kidney-related diseases including renal carcinoma, acute renal failure, and hypertension.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Mullins, Christopher V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Weisz, Ora A; Baty, Catherine J (2018) Lemmings into the sea or back across the bridge? The fate of albumin in nephrotic syndrome. Kidney Int 93:296-298
Eshbach, Megan L; Sethi, Rahil; Avula, Raghunandan et al. (2017) The transcriptome of the Didelphis virginiana opossum kidney OK proximal tubule cell line. Am J Physiol Renal Physiol 313:F585-F595
Long, Kimberly R; Shipman, Katherine E; Rbaibi, Youssef et al. (2017) Proximal tubule apical endocytosis is modulated by fluid shear stress via an mTOR-dependent pathway. Mol Biol Cell 28:2508-2517
Eshbach, Megan L; Weisz, Ora A (2017) Receptor-Mediated Endocytosis in the Proximal Tubule. Annu Rev Physiol 79:425-448
Sneddon, W Bruce; Ruiz, Giovanni W; Gallo, Luciana I et al. (2016) Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport. J Biol Chem 291:18632-42
Raghavan, Venkatesan; Weisz, Ora A (2015) Flow stimulated endocytosis in the proximal tubule. Curr Opin Nephrol Hypertens 24:359-65