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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101484-04
Application #
9394003
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Mullins, Christopher V
Project Start
2014-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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