Renal Transport Mechanisms: NaCl and Water Reabsorption Along the Nephron

Objectives

Upon completion of this chapter, the student should be able to answer the following questions:

What three processes are involved in the production of urine?
What is the composition of “normal” urine?
What transport mechanisms are responsible for sodium chloride (NaCl) reabsorption by the nephron? Where are they located along the nephron?
How is water reabsorption “coupled” to NaCl reabsorption in the proximal tubule?
Why are solutes, but not water, reabsorbed by the thick ascending limb of Henle’s loop?
What transport mechanisms are involved in the secretion of organic anions and cations? What is the physiologic relevance of these transport processes?
What transport proteins are drug targets?
What is glomerulotubular balance, and what is its physiologic importance?
What are the major hormones that regulate NaCl and water reabsorption by the kidneys? What is the nephron site of action of each hormone?
What is the aldosterone paradox?

Key Terms

Ultrafiltration

Reabsorption

Secretion

Passive transport (diffusion)

Osmosis

Solvent drag

Facilitated diffusion

Uniport

Coupled transport

Symport

Antiport

Secondary active transport

Active transport

ABC transporters

Endocytosis

Tight junctions

Lateral intercellular spaces

Type 2 diabetes mellitus

Paracellular pathway

Transcellular pathway

Fanconi syndrome

Aquaporins

Multiligand endocytic receptors

Megalin

Cubilin

Proteinuria

Tamm-Horsfall glycoprotein

Diluting segment

Zonula occludens

Bartter syndrome

Gitelman syndrome

Principal cells

Intercalated cells

Arginine vasopressin (AVP)

Angiotensin II

Aldosterone

Aldosterone-sensitive distal nephron (ASDN)

Aldosterone paradox

Atrial natriuretic peptide (ANP)

Brain natriuretic peptide (BNP)

Sgk

Urodilatin

Liddle syndrome

Pseudohypoaldosteronism (PHA)

Angiotensin-converting enzyme

Uroguanylin

Guanylin

Catecholamines

Sympathetic nerves

Dopamine

Adrenomedullin

Starling forces

Filtration fraction

Glomerulotubular balance (G-T balance)

The formation of urine involves three basic processes: (1) ultrafiltration of plasma by the glomerulus, (2) reabsorption of water and solutes from the ultrafiltrate, and (3) secretion of select solutes into the tubular fluid. Although an average of 115 to 180 L of fluid for women and 130 to 200 L of fluid for men is filtered by the human glomeruli each day, ^a

a For simplicity, we assume throughout the remainder of this section that the glomerular filtration rate is 180 L/day.

less than 1% of the filtered water and sodium chloride (NaCl) and variable amounts of other solutes are typically excreted in the urine ( Table 4.1 ). By the processes of reabsorption and secretion, the renal tubules determine the volume and composition of urine ( Table 4.2 ), which in turn allows the kidneys to precisely control the volume, osmolality, composition, and pH of the intracellular and extracellular fluid compartments. Transport proteins in cell membranes of the nephron mediate the reabsorption and secretion of solutes and water reabsorption in the kidneys. Approximately 5% to 10% of all human genes code for transport proteins, and genetic and acquired defects in transport proteins are the cause of many kidney diseases ( Table 4.3 ). Many of the transport proteins in the kidneys are important drug targets. Moreover, the kidneys are responsible for excreting numerous drugs and toxins. This chapter discusses NaCl and water reabsorption, organic anion and cation transport, the transport proteins involved in solute and water transport, and some of the factors and hormones that regulate NaCl transport. Details on acid-base transport and on K ⁺ , Ca ⁺⁺ , and inorganic phosphate (P _i ) transport and their regulation are provided in Chapter 7, Chapter 8, Chapter 9 .

TABLE 4.1

Filtration, Excretion, and Reabsorption of Water, Electrolytes, and Solutes by the Kidneys

Substance	Amount	Filtered ^∗	Excreted	Reabsorbed	% Filtered Amount Reabsorbed
Water	L/day	180	1.5	178.5	99.2
Na ⁺	mEq/day	25,200	150	25,050	99.4
K ⁺	mEq/day	720	100	620	86.1
Ca ⁺⁺	mEq/day	540	10	530	98.2
$HC O_{3}^{-}$ $HC O_{3}^{-}$	mEq/day	4320	2	4318	99.9+
Cl ^–	mEq/day	18,000	150	17,850	99.2
Glucose	mmol/day	800	0	800	100.0
Urea	g/day	56	28	25	50.0

∗ The filtered amount of any substance is calculated by multiplying the concentration of that substance in the ultrafiltrate by the glomerular filtration rate (GFR); for example, the filtered amount of Na ⁺ is calculated as [Na ⁺ ] _{ultrafiltrate} (140 mEq/L) × GFR (180 L/day) = 25,200 mEq/day.

TABLE 4.2

Composition of Urine ∗

Modified from Valtin HV: Renal physiology, ed 2, Boston, 1983, Little Brown.

Substance	Concentration
Na ⁺	50–130 mEq/L
K ⁺	20–70 mEq/L
Ammonium	30–50 mEq/L
Ca ⁺⁺	5–12 mEq/L
Mg ⁺⁺	2–18 mEq/L
Cl ^–	50–130 mEq/L
Inorganic phosphate	20–40 mEq/L
Urea	200–400 mmol/L
Creatinine	6–20 mmol/L
pH	5.0–7.0
Osmolality	500–800 mOsm/kg H ₂ O
Glucose	0
Amino acids	0
Protein	0
Blood	0
Ketones	0
Leukocytes	0
Bilirubin	0

∗ The composition and volume of the urine can vary widely in the healthy state. These values represent average ranges. Water excretion ranges between 0.5 and 1.5 L/day.

TABLE 4.3

Some Monogenic Renal Diseases Involving Transport Proteins

Modified from Nachman RH, Glassock RJ: Glomerular, vascular, and tubulointerstitial diseases. NephSAP (J Am Soc Nephrol Suppl) 9(3):119-211, 2010.

Diseases	Mode of Inheritance	Gene(s)	Transport Protein	Nephron Segment	Phenotype
Cystinuria, type I	AR	SLC3A1, SLC7A9	Amino acid symporters	Proximal tubule	Increased excretion of basic amino acids, nephrolithiasis (kidney stones)
Proximal renal tubular acidosis	AR	SLC4A4	Na ⁺ -HCO ₃ ^– symporter	Proximal tubule	Hyperchloremic metabolic acidosis
X-linked nephrolithiasis (Dent disease)	XLR	CLCN, OCRL1	Chloride channel	Distal tubule	Hypercalciuria, nephrolithiasis
Bartter syndrome	AR type I	SLC12A1	Na ⁺ /K ⁺ /2Cl ^– symporter	TAL	Hypokalemia, metabolic alkalosis, hyperaldosteronism
	AR type II	KCNJ1	ROMK channel	TAL	Hypokalemia, metabolic alkalosis, hyperaldosteronism
	AR type III	CLCNKB	Chloride channel (basolateral membrane)	TAL	Hypokalemia, metabolic alkalosis, hyperaldosteronism
	AR type IV	BSND, CLCNKA, CLCNKB	Subunit of chloride channel, chloride channels	TAL	Hypokalemia, metabolic alkalosis, hyperaldosteronism
Hypomagnesemia-hypercalciuria syndrome	AR	CLDN16	Claudin-16, also known as paracellin 1	TAL	Hypomagnesemia-hypercalciuria, nephrolithiasis
Gitelman syndrome	AR	SLC12A3	Thiazide-sensitive symporter	Distal tubule	Hypomagnesemia, hypokalemic metabolic alkalosis, hypocalciuria, hypotension
Pseudohypoaldosteronism type I	AR	SCNN1A, SCNN1B, SCNN1G	α, β, and γ subunits of ENaC	Collecting duct	Increased excretion of Na ⁺ , hyperkalemia, hypotension
Pseudohypoaldosteronism type I	AD	MLR	Mineralocorticoid receptor	Collecting duct	Increased excretion of Na ⁺ , hyperkalemia, hypotension
Liddle syndrome	AD	SCNN1B, SCNN1G	β and γ subunits of ENaC	Collecting duct	Decreased excretion of Na ⁺ , hypertension
Nephrogenic diabetes insipidus type 2	AR/AD	AQP2	Aquaporin 2 water channel	Collecting duct	Polyuria, polydipsia, plasma hyperosmolality
Distal renal tubular acidosis	AD/AR	SLC4A1	Cl ^– /HCO ₃ ^– antiporter	Collecting duct	Metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis
Distal renal tubular acidosis	AR	ATP6N1B	Subunit of H ⁺ ATPase	Collecting duct	Metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis

AD, Autosomal dominant; AR, autosomal recessive; ATPase, adenosine triphosphatase; ENaC, epithelial sodium channel; ROMK, renal outer medullary potassium; TAL, thick ascending limb of Henle’s loop; XLR, X-linked recessive.

Nephrolithiasis = kidney stones.

There are more than 300 different solute transporter genes, which form the so-called SLC (solute carrier) family of genes.

General Principles of Membrane Transport

Solutes may be transported across cell membranes by passive mechanisms, active transport mechanisms, or endocytosis. In mammals, solute movement occurs by both passive and active mechanisms, whereas all water movement is passive. The movement of a solute across a membrane is passive if it develops spontaneously and does not require direct expenditure of metabolic energy. Passive transport (diffusion) of uncharged solutes occurs from an area of higher concentration to one of lower concentration (i.e., down its chemical concentration gradient). In addition to concentration gradients, the passive diffusion of ions (but not uncharged solutes, such as glucose and urea) is affected by the electrical potential difference (i.e., electrical gradient) across cell membranes and the renal tubules. Cations (e.g., Na ⁺ and K ⁺ ) move to the negative side of the membrane, whereas anions (e.g., Cl ^– and bicarbonate [HCO ₃ ^– ]) move to the positive side of the membrane. Diffusion of water ( osmosis ) occurs through aquaporin (AQP) water channels in the cell membrane and is driven by osmotic pressure gradients. When water is reabsorbed across tubule segments, the solutes dissolved in the water also are carried along with the water. This process is called solvent drag and can account for a substantial amount of solute reabsorption across the proximal tubule. Traditionally it was thought that the biologically important gases oxygen (O ₂ ), carbon dioxide (CO ₂ ), and ammonia (NH ₃ ) diffused across the lipid bilayer of plasma membranes. It is now known that these gases also move across the membrane via specific membrane transport proteins (e.g., CO ₂ and NH ₃ have been found to cross the membrane via the AQP1 water channel).

In facilitated diffusion , transport depends on the interaction of the solute with a specific protein in the membrane that facilitates its movement across the membrane. If defined broadly, the term facilitated diffusion can be used to describe several different types of membrane transporters. For example, one form of facilitated diffusion is the diffusion of ions, such as Na ⁺ and K ⁺ , through aqueous-filled channels created by proteins that span the plasma membrane. Also, the movement of a single molecule across the membrane by a transport protein ( uniport ), such as occurs with urea and glucose, is a form of facilitated diffusion. ^b

b Some authors restrict the term facilitated diffusion to this type of transport and use as a classical example the glucose uniporter that brings glucose into cells.

Another form of facilitated diffusion is coupled transport, in which the movement of two or more solutes across a membrane depends on their interaction with a specific transport protein. Coupled transport of two or more solutes in the same direction is mediated by a symport mechanism. Examples of symport mechanisms in the kidneys include Na ⁺ -glucose, Na ⁺ –amino acid, and Na ⁺ -P _i symporters in the proximal tubule and the Na ⁺ -K ⁺ -2Cl ^– symporter in the thick ascending limb of Henle’s loop. Coupled transport of two or more solutes in opposite directions is mediated by an antiport mechanism. An Na ⁺ -H ⁺ antiporter in the proximal tubule mediates Na ⁺ reabsorption and H ⁺ secretion. With coupled transporters, at least one of the solutes usually is transported against its electrochemical gradient. The energy for this uphill movement is derived from the passive downhill movement of at least one of the other solutes into the cell. For example, in the proximal tubule, operation of the Na ⁺ -H ⁺ antiporter in the apical membrane of the cell results in the movement of H ⁺ against its electrochemical gradient out of the cell into the tubular fluid. The movement of Na ⁺ from the tubular fluid into the cell, down its electrochemical gradient, drives the uphill movement of H ⁺ . The uphill movement of H ⁺ is termed secondary active transport , to reflect the fact that the movement of H ⁺ is not directly coupled to the hydrolysis of adenosine triphosphate (ATP) (see next). Instead, the energy is derived from the gradient of the other coupled ion (in this example, Na ⁺ ).

Active transport occurs when transport is coupled directly to energy derived from metabolic processes (i.e., it consumes ATP). Active transport of solutes usually takes place from an area of lower concentration to an area of higher concentration. In the kidneys the most prevalent active transport mechanism is sodium-potassium adenosine triphosphatase (Na ⁺ -K ⁺ -ATPase) (or the sodium pump), located in the basolateral membrane of the tubular cells. The Na ⁺ -K ⁺ -ATPase is made up of several proteins that together actively move Na ⁺ out of the cell and K ⁺ into the cell. Other active transport mechanisms in the kidneys include the H ⁺ -ATPase and H ⁺ -K ⁺ -ATPase, which are responsible for H ⁺ secretion in the collecting duct (see Chapter 8 ), and the Ca ⁺⁺ -ATPase mechanism, which is responsible for Ca ⁺⁺ movement from the cell cytoplasm into the blood (see Chapter 9 ). In addition to these transport ATPases, another large group of ATP-dependent transporters exists that is called A TP- b inding c assette, or ABC transporters . To date, 7 subfamilies and more than 48 specific ABC transporters have been identified in humans. They transport a diverse group of solutes, including Cl ^– , cholesterol, bile acids, drugs, iron, and organic anions and cations.

Endocytosis is the movement of a substance across the plasma membrane by a process involving the invagination of a piece of membrane until it completely pinches off and forms a vesicle in the cytoplasm. This mechanism is important for the reabsorption of small proteins and macromolecules by the proximal tubule. Because endocytosis requires ATP, it is a form of active transport.

General Principles of Transepithelial Solute and Water Transport

As illustrated in Fig. 4.1 , tight junctions hold renal cells together. Below the tight junctions, the cells are separated by lateral intercellular spaces . The tight junctions separate the apical membranes from the basolateral membranes.

Fig. 4.1, Paracellular and transcellular transport pathways in the proximal tubule. ATP, Adenosine triphosphate.

In the nephron a substance can be reabsorbed or secreted through cells, the transcellular pathway, or between cells, the paracellular pathway (see Fig. 4.1 ). Na ⁺ reabsorption by the proximal tubule is a good example of transport by the transcellular pathway. Na ⁺ reabsorption in this nephron segment depends on the operation of the Na ⁺ -K ⁺ -ATPase (see Fig. 4.1 ). The Na ⁺ -K ⁺ -ATPase, which is located exclusively in the basolateral membrane, moves Na ⁺ out of the cell into the blood and K ⁺ into the cell. Thus the operation of the Na ⁺ -K ⁺ -ATPase lowers intracellular [Na ⁺ ] and increases intracellular [K ⁺ ]. Because intracellular [Na ⁺ ] is low (12 mEq/L) and the [Na ⁺ ] in tubular fluid is high (140 mEq/L), Na ⁺ can move across the apical membrane into the cell down this chemical gradient. This movement of Na ⁺ into the cell is coupled to the movement of other ions and molecules, either by an antiporter (e.g., Na ⁺ /H ⁺ antiporter) or symport (e.g., Na ⁺ -glucose) (see Figs. 4.2 to 4.4 ). The Na ⁺ -K ⁺ -ATPase senses the addition of Na ⁺ to the cell and is stimulated to increase its rate of Na ⁺ extrusion into the blood, thereby returning intracellular Na ⁺ to normal levels. Thus transcellular Na ⁺ reabsorption by the proximal tubule is a two-step process:

1.
Movement across the apical membrane into the cell, down a chemical concentration gradient established by the Na ⁺ -K ⁺ -ATPase
2.
Movement across the basolateral membrane against an electrochemical gradient through the Na ⁺ -K ⁺ -ATPase

Fig. 4.2, Na + transport processes in the first half of the proximal tubule. These transport mechanisms are present in all cells in the first half of the proximal tubule but are separated into different cells to simplify the discussion. (A) Operation of the Na + -H + antiporter (NHE3) in the apical membrane and the Na + -K + -ATPase and bicarbonate transporters, including the Cl – -HCO 3 – antiporter (AE2, not shown) and the Na + -HCO 3 – cotransporter ( NBC1 ; see Chapter 8 ), in the basolateral membrane, mediates NaHCO 3 reabsorption. Note that a single HCO 3 – transporter (NBC1) is illustrated for simplicity. The splice variant expressed in the proximal tubule is NBCe-1A. Carbon dioxide (CO 2 ) and water combine inside the cells to form H + and HCO 3 - in a reaction facilitated by the enzyme carbonic anhydrase (CA). (B) Operation of the Na + -glucose transporter (SGLT2) in the apical membrane, in conjunction with the Na + -K + -ATPase and glucose transporter (GLUT2) in the basolateral membrane, mediates Na + -glucose reabsorption. Inactivating mutations in the GLUT2 gene lead to decreased glucose reabsorption in the proximal tubule and glucosuria (i.e., glucose in the urine). Although not shown, Na + reabsorption also is coupled with other solutes, including amino acids, P i , and lactate. Reabsorption of these solutes is mediated by the Na + –amino acid, Na + -P i , and Na + -lactate symporters, respectively, located in the apical membrane and the Na + -K + -ATPase, amino acid, P i , and lactate transporters, respectively, located in the basolateral membrane. Three classes of amino acid transporters have been identified in the proximal tubule: two that transport Na + in conjunction with either acidic or basic amino acids and one that does not require Na + and transports basic amino acids. ATP, Adenosine triphosphate.

Fig. 4.3, Concentration of solutes in tubule fluid as a function of distance along the proximal tubule. [TF] is the concentration of the substance in tubular fluid; [P] is the concentration of the substance in plasma. Values of ([TF] / P) × 100 higher than 100 indicate that relatively less of the solute than water was reabsorbed, and values less than 100 indicate that relatively more of the substance than water was reabsorbed. HCO 3 – , Bicarbonate; P i , inorganic phosphate.

Fig. 4.4, Na + transport processes in the second half of the proximal tubule. Na + and Cl – enter the cell across the apical membrane through the operation of parallel Na + -H + (NHE3) and Cl – -base (e.g., formate, oxalate, and bicarbonate) antiporters (CFEX). More than one Cl – -base antiporter is involved in this process, but only one is depicted. The secreted H + and base combine in tubular fluid to form a H + -base complex that can recycle across the plasma membrane. Accumulation of the H + -base complex in tubular fluid establishes a H + -base concentration gradient that favors H + -base recycling across the apical plasma membrane into the cell. Inside the cell, H + and the base dissociate and recycle back across the apical plasma membrane. The net result is sodium chloride (NaCl) uptake across the apical membrane. The base may be hydroxide ions (OH – ), formate (HCO 2 – ), oxalate, HCO 3 – , or sulfate. The lumen-positive transepithelial voltage, indicated by the plus sign inside the circle in the tubular lumen, is generated by the diffusion of Cl – (lumen to blood) across the tight junction. The high Cl – concentration of tubular fluid provides the driving force for Cl – diffusion. Some glucose also is reabsorbed in the second half of the proximal tubule by a mechanism like that described in the first half of the proximal tubule, except that the Na + -glucose symporter (SGLT1) transports 2Na + with one glucose and has a higher affinity and lower capacity than the Na + -glucose symporter in the first part of the proximal tubule (i.e., SGLT2; see Fig. 4.2 ). In addition, glucose exits the cell across the basolateral membrane through GLUT1 rather than GLUT2, as in the first part of the proximal tubule (GLUT1 not shown). ATP, Adenosine triphosphate; KCC, KCl cotransporter; NHE3, sodium hydrogen exchanger 3.

The reabsorption of Ca ⁺⁺ and K ⁺ across the proximal tubule is a good example of paracellular transport. Some of the water reabsorbed across the proximal tubule traverses the paracellular pathway (see Fig. 4.1 ). Some solutes dissolved in this water, particularly Ca ⁺⁺ and K ⁺ , are entrained in the reabsorbed fluid and thereby reabsorbed by the process of solvent drag.

At the Cellular Level

The tight junction in renal epithelial cells is a specialized membrane domain that creates a barrier that regulates the paracellular diffusion of solutes across the epithelia. Tight junctions are composed of linear arrays of several integral membrane proteins, including occludins, claudins, and several members of the immunoglobulin superfamily. The tight junction complex of proteins has biophysical properties of ion channels, including the ability to allow ions to diffuse selectively across the complex based on size and charge.

NaCl, Solute, and Water Reabsorption Along the Nephron

Quantitatively the reabsorption of NaCl and water represents the major function of nephrons. Approximately 25,050 mEq/day of Na ⁺ and 178.5 L/day of water are reabsorbed by the renal tubules (see Table 4.1 ). In addition, renal transport of many other important solutes is linked either directly or indirectly to Na ⁺ reabsorption. In the following sections the NaCl and water transport processes of each nephron segment and its regulation by hormones, along with other factors, are presented.

Proximal Tubule

The proximal tubule reabsorbs approximately 67% of filtered water, Na ⁺ , Cl ^– , K ⁺ , and other solutes. In addition, the proximal tubule reabsorbs virtually all the glucose and amino acids filtered by the glomerulus, as well as most of the HCO ₃ ^– . The key element in proximal tubule reabsorption is the Na ⁺ -K ⁺ -ATPase in the basolateral membrane. The reabsorption of every substance, including water, is linked in some manner to the operation of the Na ⁺ -K ⁺ -ATPase.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here