Protein endocytosis in the proximal tubule is facilitated by apical membrane proteins that specifically bind proteins and peptides in the tubule fluid. These receptors, known as multiligand endocytic receptors, have the ability to bind a wide range of peptides and proteins, enabling their endocytosis. Megalin and cubilin are glycoproteins that play a role in protein and peptide endocytosis in the proximal tubule. Megalin belongs to the low-density lipoprotein receptor gene family.

The mechanisms of organic anion (OA-) transport across the proximal tubule are illustrated in Fig. 34.5. These secretory pathways have high transport rates, low specificity (meaning they transport various OA-s), and are responsible for secreting the listed OA-s mentioned in Box 34.1.

OA-s are taken up into the cell through the basolateral membrane, against their chemical gradient, in exchange for α-ketoglutarate (α-KG). This transport is facilitated by several OA-/α-KG antiporters, including OAT1, OAT2, and OAT3. α-KG accumulates inside the cells through glutamate metabolism and a Na+/α-KG symporter (NaDC3) present in the basolateral membrane. Consequently, the uptake of OA-s into the cell against an electrochemical gradient is coupled with the exit of α-KG out of the cell, driven by the Na+/α-KG symporter mechanism.

Urinalysis is a routine and essential tool for the detection of kidney disease. It involves a comprehensive analysis of urine, including macroscopic, microscopic, and biochemical assessments. This analysis entails visually examining the urine, microscopically evaluating the urinary sediment, and biochemically assessing urinary composition using dipstick reagent strips. The dipstick test is a rapid (i.e., <5 minutes) and cost-effective method that assesses urine pH and the presence of various substances, such as bilirubin, blood, glucose, ketones, and protein. It is normal to detect trace amounts of protein in urine, particularly in concentrated urine. Urinary proteins originate from two primary sources: (1) filtration exceeding the reabsorptive capacity of the proximal tubule, and (2) synthesis and secretion of Tamm-Horsfall glycoprotein by the thick ascending limb of Henle's loop. As protein reabsorption occurs "upstream" of the thick ascending limb (i.e., in the proximal tubule), the secreted Tamm-Horsfall glycoprotein appears in the urine. However, proteinuria in amounts greater than trace is often indicative of renal disease.

The luminal membrane facilitates the exit of OA-s into the tubular fluid through the action of multidrug resistance proteins 2 and 4 (MRP2/4) and breast cancer resistance protein 1 (BCRP). These transporters require adenosine triphosphate (ATP) to function properly. Recent studies have shown that OAT4 is responsible for reabsorbing the organic anion urate, which is the end product of purine catabolism, in the proximal tubule (refer to Fig. 34.5).

The secretion of organic cations (OC+) across the proximal tubule is depicted in Fig. 34.6. OC+s enter the cell through the basolateral membrane primarily via OCT2. The uptake of OC+s into the cell against their chemical concentration gradient is driven by the cell's negative potential difference. OC+s exit the cell through the apical membrane in exchange for H+, facilitated by electrically neutral multidrug and toxin transporters (MATE1 and MATE2-K), as well as multidrug resistance protein (MDR1), which requires ATP.
The endocytosis of proteins by the proximal tubule is mediated by apical membrane proteins that specifically bind proteins and peptides in tubule fluid. These receptors, called multiligand endocytic receptors, can bind a wide range of peptides and proteins and thereby mediate their endocytosis. Megalin and cubilin mediate protein and peptide endocytosis in the proximal tubule. Both are glycoproteins, with megalin being a member of the low-density lipoprotein receptor gene family.
Fig. 34.5 illustrates the mechanisms of organic anion (OA−) transport across the proximal tubule. These secretory pathways have maximum transport rates, low specificity (i.e., they transport many OA−s), and are responsible for secretion of the OA−s listed in
Box 34.1.
OA−s are taken up into the cell across the basolateral membrane against their chemical gradient in exchange for α-ketoglutarate (α-KG) via several OA−/α-KG antiporters, including OAT1, OAT2, and OAT3. α-KG accumulates inside the cells via metabolism of glutamate and by a Na+/α-KG symporter (i.e., the Na+/dicarboxylate transporter [NaDC3]) also present in the basolateral membrane. Thus uptake of OA− into the cell against an electrochemical gradient is coupled to the
Urinalysis is an important and routine tool for detection of kidney disease. A thorough analysis of urine includes macroscopic, microscopic, and biochemical assessments. This is performed by visual assessment of the urine, microscopic examination of urinary sediment, and biochemical evaluation of urinary composition using dipstick reagent strips. The dipstick test is both inexpensive and fast (i.e., <5 minutes) and tests urine for both pH and the presence of many substances (e.g., bilirubin, blood, glucose, ketones, protein). It is normal to find trace amounts of protein in urine, particularly concentrated urine. Urinary proteins are derived from two principal sources: (1) filtration exceeding the reabsorptive capacity of the proximal tubule and (2) synthesis and secretion of Tamm-Horsfall glycoprotein by the thick ascending limb of Henle’s loop. Because the mechanism for protein reabsorption is “upstream” of the thick ascending limb (i.e., in the proximal tubule), the secreted Tamm-Horsfall glycoprotein appears in urine. However, proteinuria in greater than trace amounts is often indicative of renal disease.
exit of α-KG out of the cell, down its chemical gradient generated by the Na+/α-KG symporter mechanism. The exit of OA−s across the luminal membrane into the tubular fluid are mediated by multidrug resistance proteins 2 and 4 (MRP2/4) and breast cancer resistance protein 1 (BCRP), which require adenosine triphosphate (ATP) for their operation. Recent studies reveal that OAT4 mediates reabsorption of the organic anion urate, the end product of purine catabolism, by the proximal tubule (see
Fig. 34.5 •Fig. 34.6 Organic cation (OC+) secretion across the proximal tubule. OC+s enter the cell across the basolateral membrane primarily by OCT2. Uptake of OC+s into the cell against their chemical concentration gradient is driven by the cell-negative potential difference. OC+s leave the cell across the apical membrane in exchange with H+by electrically neutral multidrug and toxin transporters (MATE1 and MATE2-K) and by multidrug resistance protein (MDR1), which requires ATP. ATP OCT2MATE MDR1 Na+ OC+ OC+ H+ K+ Blood Tubular fluid OC+ ATP ADP