The proximal tubule (PT) of the kidney is the primary site for reabsorption of ions, solutes, and filtered low molecular weight (LMW) proteins. PT cells acutely modulate ion transport capacity in respond to changes in fluid shear stress (FSS) that accompany alterations in glomerular filtration rate. This proposal is focused on understanding whether PT cells also adjust the capacity of megalin-and cubilin- mediated endocytosis of LMW proteins in response to altered demand. Defective uptake of these proteins leads to tubular proteinuria, which can eventually lead to renal failure. We have discovered that apical endocytosis of the megalin/cubilin ligand albumin as well as fluid phase markers is markedly increased upon exposure of PT cells to FSS. Moreover, primary cilia are required for this response.
The aims of this proposal are to (1) determine how changes in FSS are transduced into effects on apical endocytosis and (2) determine whether defective modulation of flow-dependent endocytosis contributes to LMW proteinuria observed in animal models for Lowe Syndrome, an X- linked disorder that may involve defects in ciliogenesis. We have assembled an outstanding team of investigators with essential expertise to carry out this broad range of studies. The results of our experiments will provide key information about a newly discovered pathway that plays an essential role in maintaining kidney function.
The proximal tubule of kidney reabsorbs water, ions, metabolites, and filtered proteins from the forming urine to regulate blood pressure. The volume of filtered plasma passing through this kidney segment can vary significantly and acutely. It is known that ion transport rates in the proximal tubule vary with changes in filtration rate. We have now discovered that proximal tubule cells also adjust their capacity to internalize proteins and small molecules in response to changes in filtration rate. We are interested in understanding how cells sense changes in filtration and how this information is translated into changes in protein recovery important for maintaining kidney function. The results of our research will provide important new information that may help in designing therapies to combat kidney-related disorders where the response to filtration is compromised, including Lowe syndrome, diabetes, and chronic kidney disease.
|Eshbach, Megan L; Kaur, Amandeep; Rbaibi, Youssef et al. (2017) Hemoglobin inhibits albumin uptake by proximal tubule cells: implications for sickle cell disease. Am J Physiol Cell Physiol 312:C733-C740|
|Eshbach, Megan L; Weisz, Ora A (2017) Receptor-Mediated Endocytosis in the Proximal Tubule. Annu Rev Physiol 79:425-448|
|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|
|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 (2016) Discerning the role of mechanosensors in regulating proximal tubule function. Am J Physiol Renal Physiol 310:F1-5|
|Raghavan, Venkatesan; Weisz, Ora A (2015) Flow stimulated endocytosis in the proximal tubule. Curr Opin Nephrol Hypertens 24:359-65|