Proximal tubule apical endocytosis is modulated by fluid shear stress via an mTOR-dependent pathway
نویسندگان
چکیده
Cells lining the proximal tubule (PT) have unique membrane specializations that are required to maintain the high-capacity ion transport and endocytic functions of this nephron segment. PT cells in vivo acutely regulate ion transport in response to changes in glomerular filtration rate (GFR) to maintain glomerulotubular balance. PT cells in culture up-regulate endocytic capacity in response to acute changes in fluid shear stress (FSS); however, it is not known whether GFR modulates PT endocytosis to enable maximally efficient uptake of filtered proteins in vivo. Here, we show that cells cultured under continuous FSS develop an expanded apical endocytic pathway and increased endocytic capacity and lysosomal biogenesis. Furthermore, endocytic capacity in fully differentiated cells is rapidly modulated by changes in FSS. PT cells exposed to continuous FSS also acquired an extensive brush border and basolateral membrane invaginations resembling those observed in vivo. Culture under suboptimal levels of FSS led to intermediate phenotypes, suggesting a threshold effect. Cells exposed to FSS expressed higher levels of key proteins necessary for PT function, including ion transporters, receptors, and membrane-trafficking machinery, and increased adenine nucleotide levels. Inhibition of the mechanistic target of rapamycin (mTOR) using rapamycin prevented the increase in cellular energy levels, lysosomal biogenesis, and endocytic uptake, suggesting that these represent a coordinated differentiation program. In contrast, rapamycin did not prevent the FSS-induced increase in Na+/K+-ATPase levels. Our data suggest that rapid tuning of the endocytic response by changes in FSS may contribute to glomerulotubular balance in vivo. Moreover, FSS provides an essential stimulus in the differentiation of PT cells via separate pathways that up-regulate endocytosis and ion transport capacity. Variations in FSS may also contribute to the maturation of PT cells during kidney development and during repair after kidney injury.
منابع مشابه
Correction for “ Shear stress - dependent regulation of apical en - docytosis in renal proximal tubule cells mediated by primary cilia , ”
CELL BIOLOGY Correction for “Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia,” by Venkatesan Raghavan, Youssef Rbaibi, Núria M. Pastor-Soler, Marcelo D. Carattino, and Ora A. Weisz, which appeared in issue 23, June 10, 2014, of Proc Natl Acad Sci USA (111:8506–8511; first published May 27, 2014; 10.1073/pnas.1402195111). The autho...
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