Proximal Tubule Cell Hypothesis for Cardiorenal Syndrome in Diabetes

Figure 2

Endocytic receptors and transporters involved in the uptake of substances at the apical membranes of proximal tubule cells (PTCs). At apical membranes of PTCs, megalin and the cubilin-amnionless complex are involved in endcytosis of protein ligands. Megalin facilitates uptake of various ligands including vitamin D/vitamin D-binding protein (DBP), vitamin B₁₂/transcobalamin (TC), folate/folate-binding protein (FBP) complexes, and selenoprotein P. Similarly, cubilin facilitates uptake of the vitamin D/DBP complex. Type IIa Na/Pi cotransporter (NaPi-IIa) and Na⁺/H⁺ exchanger isoform 3 (NHE3) are primarily involved in the uptake of phosphate and sodium, respectively. Homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) may be taken up by cationic amino acid transporters (CATs) and metabolized in PTCs. Dysregulation of the uptake or metabolism of these substances in PTCs in patients with CKD, especially with diabetic nephropathy, is likely to be involved in the mechanism that promotes the development of CVD.