Proximal tubule cell hypothesis for cardiorenal syndrome in diabetes

Abstract

Incidence of cardiovascular disease (CVD) is remarkably high among patients with chronic kidney disease (CKD), even in the early microalbuminuric stages with normal glomerular filtration rates. Proximal tubule cells (PTCs) mediate metabolism and urinary excretion of vasculotoxic substances via apical and basolateral receptors and transporters. These cells also retrieve vasculoprotective substances from circulation or synthesize them for release into the circulation. PTCs are also involved in the uptake of sodium and phosphate, which are critical for hemodynamic regulation and maintaining the mineral balance, respectively. Dysregulation of PTC functions in CKD is likely to be associated with the development of CVD and is linked to the progression to end-stage renal disease. In particular, PTC dysfunction occurs early in diabetic nephropathy, a leading cause of CKD. It is therefore important to elucidate the mechanisms of PTC dysfunction to develop therapeutic strategies for treating cardiorenal syndrome in diabetes.

Figure 1

Normal functions of proximal tubule cells (PTCs) and structural changes around the cells in the early stages of diabetic nephropathy. Normal functions of PTCs include (1) reabsorption and intracellular processing of glomerular-filtered substances via apical membrane receptors, transporters, and channels; (2) uptake of substances via basolateral membrane transporters followed by metabolism or secretion into the urinary space; (3) synthesis of bioactive substances that are released to peritubular capillaries. These functions are impaired in diabetic nephropathy even at the early stages in which PTCs are hypertrophied with increased metabolic demands and are phenotypically altered. In addition, tubular basement membranes (TBMs) are thickened, and interstitial spaces are expanded with fibrosis, alienating PTCs from interacting with peritubular capillaries.

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.

Figure 3

Intracellular synthesis and metabolism of homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) and their biochemical link. Vitamin B₁₂ serves as a cofactor for the formation of methionine (Met) from homocysteine (Hcy) by methionine synthase using 5-methyl-tetrahydrofolate (5-MTHF), the dominant folate form in serum. S-adenosylmethionine (AdoMet) is the intermediate in this reaction and serves as the methyl donor to form S-adenosylhomocysteine (AdoHcy). Hcy is either remethylated to Met or transsulfurated to cysteine. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS). ADMA is formed by methylation of arginine residues in proteins with protein methyltransferase (PRMT) and released after proteolysis. Metabolism of ADMA is mediated by dimethylarginine dimethylaminohydrolases (DDAHs), which are downregulated by reactive oxygen species and Hcy.