Question

7) Considering the magnitude of glomerular filtration, the extent of tubular reabsorption is tremendous:
e.g., the tubules typically reabsorb >99% of the filtered water (47 gallons/day), 100% of filtered sugar
(2.5 lbs/day), & ~99.5% of the filtered salt (0.65 lb/day).
Describe the processes involved in passive and active reabsorption. Which membrane (i.e., which side
of the tubule cell) contains the Na + K + pumps? How does this pump effect [Na + ] in the epithelial cell?

Answer 1

Na⁺ K ⁺ ATPase, a sodium pump (active transporter) is located on the opposite side of the epithelial cell .

It allows three sodium ions out of cell for two potassium ions moves into the cell

The principal processes that determine the urinary excretion of a drug arc

1. Glomerular filtration.
2. Active tubular secretion.
3. Active or passive tubular reabsorption

Glomerular filtration is a non-selective, unidirectional process whereby most compounds, ionized or unionised, are altered except those that are bound to plasma proteins or blood cells and thus behave as macromolecules .

The glomerulus also acts as a negatively charged selective barrier promoting retention of anionic compounds. The driving force for filtration through the glomerulus is the hydrostatic pressure of the blood flowing in the capillaries. Out of the 25% of cardiac output or 1.2 litres of blood/min that goes to the kidneys via renal artery, only 10% or 120 to 13O ml/min is filtered through the glomerulus the rate being called as glomerular filtration rate .

Tubular reabsorption occurs after the glomerular filtration of drugs. It takes place all along the renal tubule. An agent such as glucose that is completely reabsorbed after filtration has a clearance value of zero.

Tubular reabsorption can either be an:

1. Active process, or
2. Passive process.

Active tubular reabsorption is commonly seen with high threshold endogenous substances or nutrients that the body needs to conserve such as electrolytes, glucose etc.

Passive tubular reabsorption is common for a large number of exogenous substances including drugs. The driving force for such a process i.e. the concentration gradient is established by the back diffusion or reabsorption of water along with sodium and other inorganic ions.

The primary determinant in the passive reabsorption of drugs is their lipophilicity. Lipophilic substances are extensively reabsorbed while polar molecules arc not. rebsorption also depends on

1. pH of the urine.
2. pK_a of the drug.
3. Urine flow rate.

The mechanisms involved in ion movement across tubular cells are complex and involve a variety of energy dependent transmembrane pumps as well as channels in between the loose fitting cells of the proximal tubule .

All Na+ that enters tubular cells through the luminal membrane is pumped out of it into the renal interstitial at the basolateral membrane by Na-K-ATPase energised Na⁺-K⁺ antiporter ,Because there is a large intracellular to extracellular gradient for K⁺, it diffuses out through K channels to be recirculated by the Na⁺-K⁺ antiporter.

In Proximal tubule four mechanisms of Na⁺ transport have been defined in this segment.

1. Direct entry of Na⁺ along a favorable electrochemical gradient. This is electrogenic.
2. Transport of Na⁺ and K⁺ coupled to active reabsorption of glucose, amino acids, other organic anions and PO⁴” through specific symporters.
3. Exchange with H⁺: The PT cells secrete H⁺ with the help of carbonic anhydrase (CAse) .H⁺ ion exchanges with Na⁺ present in the tubular fluid through Na⁺-H⁺ antiporter located in the luminal membrane and forms H₂C0₃ by combining with HC0₃ left behind. This H₂C0₃ is broken into H₂0 + C0₂ by brush border CAse; both C0₂ and H₂0 diffuse inside the cell and recombine to form HCO3 (intracellular CAse catalysed reaction) which is the source of H⁺. The dissociated HC0₃ in the cell is transported to the cortical e.c.f. by basolateral membrane.
4. Major portion of filtered K+ is reabsorbed in the PT.An isotonic tubular fluid with major changes in composition enters the thin descending limb of loop of Henle.

Ascending limb of loop of Henle (Asc LH) The thick Asc LH can be distinguished into two distinct portions.

(i) Medullary part lined by cuboidal cells.

( ii) Cortical part lined by flattened cells.

Both portions are relatively impermeable to water but absorb salt actively and thus dilute the tubular fluid.

In medullary portion transport takes place Stochiometric ratio of Na+-K+-2 Cl and is noneleetrogenic.

The Na+ that enters the cell is pumped to the e.c.f. by Na+ K+ ATPase at the basolateral membrane .

In addition, a Na+-CI” symporter moves CL down its electrochemical gradient into the e.c.f. and carries Na+ along.

As the tubular fluid traverses the Asc LH it progressively becomes hypotonic.

The accumulation of NaCl in the medullary interstitium without accompanying water makes it hypertonic:- a corticomedullary osmotic gradient is set up. This draws in water from the descending limb of loop of Henle (this thin segment has high osmotic water permeability but lacks active NaCl transport) so that the fluid that enters Asc LH becomes hypotonic.