Biochemistry of Respiration and RENAL Function

TRANSPORT OF GASSES:

● Major activity in the lungs is the process of respiration, the process of gas exchange.The
function of respiration is to provide oxygen for use by body cells during cellular respiration and to
eliminate carbon dioxide, a waste product of cellular respiration, from the body.
● For the exchange of oxygen and carbon dioxide to occur, both gasses must be transported
between the external and internal respiration sites.
● Carbon dioxide is more soluble than oxygen in blood, both gasses require a specialized
transport system for the majority of the gas molecules to be moved between the lungs and other
tissues.
OXYGEN TRANSPORT IN THE BLOOD

● A small amount of oxygen does dissolve in the blood and is transported in the bloodstream,
but it is only about 1.5% of the total amount.
● The majority of oxygen molecules are carried from the lungs to the body’s tissues by a
specialized transport system, which relies on the erythrocyte—the red blood cell.
● Erythrocytes contain a metalloprotein, hemoglobin, which serves to bind oxygen molecules
to the erythrocyte.
● Heme is the portion of hemoglobin that contains iron, and it is heme that binds oxygen.
One hemoglobin molecule contains iron-containing Heme molecules, and because of this, each
hemoglobin molecule is capable of carrying up to four molecules of oxygen.
● As oxygen diffuses across the respiratory membrane from the alveolus to the capillary, it
also diffuses into the red blood cell and is bound by hemoglobin. The following reversible chemical
reaction describes the production of the final product, oxyhemoglobin (Hb–O2), which is formed
when oxygen binds to hemoglobin. Oxyhemoglobin is a bright red-colored molecule that
contributes to the bright red color of oxygenated blood.
Hb + O2 ↔ Hb − O2

FUNCTION OF HEMOGLOBIN

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● Hemoglobin is composed of subunits, a protein structure that is referred to as a quaternary
structure. Each of the four subunits that make up hemoglobin is arranged in a ring-like fashion,
with an iron atom covalently bound to the heme in the center of each subunit. Binding of the first
oxygen molecule causes a conformational change in hemoglobin that allows the second molecule
of oxygen to bind more readily.
● As each molecule of oxygen is bound, it further facilitates the binding of the next molecule,
until all four heme sites are occupied by oxygen. The opposite occurs as well: After the first oxygen
molecule dissociates and is “dropped off” at the tissues, the next oxygen molecule dissociates more
readily.
● When all four heme sites are occupied, the hemoglobin is said to be saturated. When one
to three heme sites are occupied, the hemoglobin is said to be partially saturated. Therefore, when
considering the blood as a whole, the percent of the available heme units that are bound to oxygen
at a given time is called hemoglobin saturation.
● Hemoglobin saturation of 100 percent means that every heme unit in all of the erythrocytes
of the body is bound to oxygen.In a healthy individual with normal hemoglobin levels, hemoglobin
saturation generally ranges from 95 percent to 99 percent.
OXYGEN DISSOCIATION FROM HEMOGLOBIN

● An oxygen–hemoglobin dissociation curve is a graph that describes the relationship of

partial pressure to the binding of oxygen to heme and its subsequent dissociation from heme.
● Gases travel from an area of higher partial pressure to an area of lower partial pressure.The
affinity of an oxygen molecule for heme increases as more oxygen molecules are bound.
● Therefore, in the oxygen–hemoglobin saturation curve, as the partial pressure of oxygen
increases, a proportionately greater number of oxygen molecules are bound by heme.
● The oxygen–hemoglobin saturation/dissociation curve also shows that the lower the partial
pressure of oxygen, the fewer oxygen molecules are bound to heme.

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● As a result, the partial pressure of oxygen plays a major role in determining the degree of
binding of oxygen to heme at the site of the respiratory membrane, as well as the degree of
dissociation of oxygen from heme at the site of body tissues.
● Factors other than partial pressure also affect the oxygen–hemoglobin
saturation/dissociation curve. For example, a higher temperature promotes hemoglobin and
oxygen to dissociate faster, whereas a lower temperature inhibits dissociation.

● The human body tightly regulates temperature, so this factor may not affect gas exchange
throughout the body. The exception to this is in highly active tissues, which may release a larger
amount of energy than is given off as heat. As a result, oxygen readily dissociates from
hemoglobin, which is a mechanism that helps to provide active tissues with more oxygen .

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● Certain hormones, such as androgens, epinephrine, thyroid hormones, and growth
hormone, can affect the oxygen–hemoglobin saturation/dissociation curve by stimulating the
production of a compound called 2,3-bisphosphoglycerate (BPG) by erythrocytes.
● BPG is a byproduct of glycolysis. Because erythrocytes do not contain mitochondria,
glycolysis is the sole method by which these cells produce ATP.
● BPG promotes the dissociation of oxygen from hemoglobin. Therefore, the greater the
concentration of BPG, the more readily oxygen dissociates from hemoglobin, despite its partial
pressure.
● The pH of the blood is another factor that influences the oxygen–hemoglobin
saturation/dissociation curve .

● The Bohr effect is a phenomenon that arises from the relationship between pH and
oxygen’s affinity for hemoglobin: A lower, more acidic pH promotes oxygen dissociation from
hemoglobin.
● In contrast, a higher, or more basic, pH inhibits oxygen dissociation from hemoglobin. The
greater the amount of carbon dioxide in the blood, the more molecules that must be converted,
which in turn generates hydrogen ions and thus lowers blood pH.
● Furthermore, blood pH may become more acidic when certain byproducts of cell
metabolism, such as lactic acid, carbonic acid, and carbon dioxide, are released into the
bloodstream.

COOPERATIVITY AND HILL PLOT

Cooperativity is a complex subject; one model is the interconversion of the hemoglobin between
two states—the T (tense) and the R (relaxed) conformations—of the molecule. The R state has

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higher affinity for oxygen. Under conditions where pO 2 is high (such as in the lungs), the R state
is favored; in conditions where pO 2 is low (as in exercising muscle), the T state is favored.

Quantitatively, the binding curve of a complex protein like hemoglobin is described by the
approximation:

where n is the number of interacting subunits. The equation can be manipulated into logarithmic
form:

● A graph of this equation yields a Hill plot (named after the British physiologist who first
described it), as shown in Figure . Hill plots of log [ Y/(1 ‐ Y)] versus log(pO 2) are linear, over at
least part of the range, with slope n (sometimes called a Hill coefficient), which is the minimal
number of interacting subunits.
● Hemoglobin has a tetrameric quaternary structure made up of two alpha and two beta
subunits, which may bind allosterically up to four oxygen molecules in a positively cooperative
manner with a Hill coefficient of n=2.7–3.0, the actual value depending on the physicochemical
state of the hemoglobin solution. Myoglobin, which only has one subunit, the slope must be 1.

CARBON DIOXIDE TRANSPORT IN THE BLOOD

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⮚ Carbon dioxide is transported by three major mechanisms.
1) The first mechanism of carbon dioxide transport is by blood plasma, as some carbon
dioxide molecules dissolve in the blood.
2) The second mechanism is transport in the form of bicarbonate (HCO3–), which also
dissolves in plasma.
3) The third mechanism of carbon dioxide transport is similar to the transport of oxygen by
erythrocytes .

DISSOLVED CARBON DIOXIDE

● Carbon dioxide is not considered to be highly soluble in blood, a small fraction—about 7

to 10 percent—of the carbon dioxide that diffuses into the blood from the tissues dissolves in
plasma. The dissolved carbon dioxide then travels in the bloodstream and when the blood reaches
the pulmonary capillaries, the dissolved carbon dioxide diffuses across the respiratory membrane
into the alveoli, where it is then exhaled during pulmonary ventilation.
BICARBONATE BUFFER

● A large fraction—about 70 percent—of the carbon dioxide molecules that diffuse into the
blood is transported to the lungs as bicarbonate. Most bicarbonate is produced in erythrocytes after
carbon dioxide diffuses into the capillaries, and subsequently into red blood cells.
● Carbonic anhydrase (CA) causes carbon dioxide and water to form carbonic acid (H2CO3),
which dissociates into two ions: bicarbonate (HCO3–) and hydrogen (H+). The following formula
depicts this reaction:
CO2 + H2O CA ↔ H2CO3↔H+ + HCO3−
● Bicarbonate tends to build up in the erythrocytes, so that there is a greater concentration of
bicarbonate in the erythrocytes than in the surrounding blood plasma. As a result, some of the

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bicarbonate will leave the erythrocytes and move down its concentration gradient into the plasma
in exchange for chloride (Cl–) ions.
● This phenomenon is referred to as the chloride shift and occurs because by exchanging
one negative ion for another negative ion, neither the electrical charge of the erythrocytes nor that
of the blood is altered.
● At the pulmonary capillaries, the chemical reaction that produced bicarbonate is reversed,
and carbon dioxide and water are the products. Much of the bicarbonate in the plasma re-enters
the erythrocytes in exchange for chloride ions.
● Hydrogen ions and bicarbonate ions join to form carbonic acid, which is converted into
carbon dioxide and water by carbonic anhydrase. Carbon dioxide diffuses out of the erythrocytes
and into the plasma, where it can further diffuse across the respiratory membrane into the alveoli
to be exhaled during pulmonary ventilation.
CARBAMINOHEMOGLOBIN:

● About 20 percent of carbon dioxide is bound by hemoglobin and is transported to the lungs.
Carbon dioxide does not bind to iron as oxygen does; instead, carbon dioxide binds amino acid
moieties on the globin portions of hemoglobin to form carbaminohemoglobin, which forms when
hemoglobin and carbon dioxide bind.
● When hemoglobin is not transporting oxygen, it tends to have a bluish-purple tone to it,
creating the darker maroon color typical of deoxygenated blood. The following formula depicts
this reversible reaction:

CO2 + Hb ↔ HbCO2

● Similar to the transport of oxygen by heme, the binding and dissociation of carbon dioxide
to and from hemoglobin is dependent on the partial pressure of carbon dioxide.
● Because carbon dioxide is released from the lungs, blood that leaves the lungs and reaches
body tissues has a lower partial pressure of carbon dioxide than is found in the tissues.
● As a result, carbon dioxide leaves the tissues because of its higher partial pressure, enters
the blood, and then moves into red blood cells, binding to hemoglobin. In contrast, in the
pulmonary capillaries, the partial pressure of carbon dioxide is high compared to within the alveoli.
● As a result, carbon dioxide dissociates readily from hemoglobin and diffuses across the
respiratory membrane into the air.

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● In addition to the partial pressure of carbon dioxide, the oxygen saturation of hemoglobin
and the partial pressure of oxygen in the blood also influence the affinity of hemoglobin for carbon
dioxide.
● The Haldane effect is a phenomenon that arises from the relationship between the partial
pressure of oxygen and the affinity of hemoglobin for carbon dioxide. Hemoglobin that is saturated
with oxygen does not readily bind carbon dioxide. However, when oxygen is not bound to heme
and the partial pressure of oxygen is low, hemoglobin readily binds to carbon dioxide.
STRUCTURE OF NEPHRON:

Nephron is the structural and functional unit of the kidney.Each nephron has two major portions:

(1)A Renal corpuscle (Malpighian body)

(2)A Renal tubule

1. Renal corpuscles (Malpighian body):A renal corpuscle consists of a glomerulus surrounded

by a glomerular capsule (Bowman’s capsule).The glomerulus is a capillary network that arises
from an afferent arteriole and empties into an efferent arteriole. The diameter of the efferent
arteriole is smaller than that of the afferent arteriole, which helps maintain a fairly high blood
pressure in the glomerulus.Bowman’s capsule is double walled cup like structure and it encloses
the glomerulus. The wall of glomerulus and the Bowman’s capsule consists of a single layer of
flattened epithelial cells.Glomerular capsule consists of three layers

i) Outer parietal layer consists of squamous epithelium cells with minute pore of 12 nm diameter
called fenestrations

ii) Middle basement membrane which is selectively permeable

iii) The inner visceral layer of large nucleated cells called podocytes. Podocytes bear finger-like
projections known as podocels. The area between the two podocels is a filtration slit underlying
the basement membrane.

2. Renal tubules:The renal tubule continues from Bowman’s capsule and consists of the following
parts: proximal convoluted tubule (in the renal cortex), loop of Henle (in the renal medulla), and
distal convoluted tubule (in the renal cortex).

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i) Proximal convoluted tubules (PCT): it is the proximal part of renal tubules next to Bowman’s
capsule. It is lined with microvilli. Maximum reabsorption of water, glucose, amino acids and
electrolytes takes place here.

ii) Loop of Henle: It is a U shaped middle portion of renal tubules. It is composed of an ascending
and descending loop. Ascending loop is thick walled and impermeable to water while the
descending loop is thin walled and permeable to water. Counter current mechanism plays a crucial
role in the loop of Henle.

iii) Distal convoluted tubules (DCT): It is the distal part of renal tubules that leads to collecting
ducts. It is similar in structure and function with PCT.

iv) Collecting tubules: It is not a part of nephron rather it is a part of the kidney. The distal
convoluted tubules from several nephrons empty into a collecting tubule. Several collecting
tubules then unite to form a papillary duct that empties urine into a minor calyx and then into major
calyx and finally into renal pelvis.

Mechanism of
urine
formation:

Urine is the
liquid waste product of the human body. It contains urea, uric acid, salts, water and other waste
products that are the result of various metabolic processes occurring in the body. It is formed in
the primary excretory organs– the kidneys.Millions of nephrons are involved in the process of
urine formation.

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The formation process occurs in 3 steps or phases:

(1)Glomerular Filtration

(2)Tubular Reabsorption

(3)Tubular Secretion

Glomerular Filtration:

This process occurs in the glomerular capillaries. The process of filtration leads to the formation
of an ultrafiltrate. The blood gushes into these capillaries with high pressure and gets filtered across
the thin capillary walls. Everything except the blood cells and proteins are pushed into the capsular
space of the Bowman’s capsule to form the ultrafiltrate. The glomerular filtration rate (GFR) is
125ml/min or 180 Litres/day.

Tubular Reabsorption

During glomerular filtration, all substances except blood cells and proteins are pushed through the
capillaries at high pressure. At the level of the Proximal Convoluted Tubule(PCT), some of the

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substances from the filtrate are reabsorbed. These include sodium chloride, potassium, glucose,
amino acids, bicarbonate, and 75% of water.

Absorption of some substances is passive, some substances are actively transported while others
are co-transported. The absorption depends upon the permeability of different parts of the nephron.
The distal convoluted tubule shows selective absorption. The substances and water which is
reabsorbed are taken up by the peritubular capillaries to be returned to the blood.

Tubular Secretion

The peritubular capillaries that help in transporting the reabsorbed substances into the bloodstream,
also help in actively secreting substances like H+ ions, K+ ions. Whenever excess K+ is secreted
into the filtrate, Na+ ions are actively reabsorbed to maintain the Na-K balance. Some drugs are
not filtered in the glomerulus and so are actively secreted into the filtrate during the tubular
secretion phase.

Acid-Base Balance

● Blood needs the right balance of acidic and basic (alkaline) compounds to function properly.
This is called the acid-base balance. Kidneys and lungs work to maintain the acid-base balance.
Even slight variations from the normal range can have significant effects on vital organs.
● Acid and alkaline levels are measured on a pH scale. An increase in acidity causes pH
levels to fall. An increase in alkaline causes pH levels to rise.When the levels of acid in blood are
too high, it’s called acidosis. When blood is too alkaline, it is called alkalosis.Respiratory acidosis
and alkalosis are due to a problem with the lungs. Metabolic acidosis and alkalosis are due to a
problem with the kidneys.

Metabolic acidosis:Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically

with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low
or slightly subnormal. Metabolic acidosis is categorized as high or normal anion gap based on the
presence or absence of unmeasured anions in serum. Causes include accumulation of ketones and
lactic acid, renal failure, and drug or toxin ingestion (high anion gap) and GI or renal HCO3− loss

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(normal anion gap). Symptoms and signs in severe cases include nausea and vomiting, lethargy,
and hyperpnea.

Respiratory acidosis:Respiratory acidosis is a condition that occurs when the lungs can’t remove
enough of the carbon dioxide (CO2) produced by the body. Excess CO2 causes the pH of blood
and other body fluids to decrease, making them too acidic.

Respiratory alkalosis :The primary abnormalities in respiratory alkalosis is a decrease in H2CO3

concentration .This may occur due to prolonged hyperventilation resulting in increased exhalation
of CO2 by the lungs.

Metabolic alkalosis:The primary abnormalities in metabolic alkalosis is an increase in HCO3-

concentration.This may occur due to excessive vomiting or an excessive intake of sodium
bicarbonate for therapeutic purposes.

Kidneys and Acid–Base Balance

The kidneys have two very important roles in maintaining the acid–base balance:

1. They reabsorb bicarbonate from urine.

2. They excrete hydrogen ions into urine.
● The kidneys are slower to compensate than the lungs, but renal physiology has several
powerful mechanisms to control pH by the excretion of excess acid or base. The major,
homeostatic control point for maintaining a stable pH balance is renal excretion.

● Bicarbonate (HCO3−) does not have a transporter, so its reabsorption involves a series of
reactions in the tubule lumen and tubular epithelium. In response to acidosis, the tubular cells
reabsorb more bicarbonate from the tubular fluid, and the collecting duct cells secrete more
hydrogen and generate more bicarbonate, and ammoniagenesis leads to an increase in the
formation of the NH3 buffer.
● In response to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen
ion secretion from the tubular epithelial cells, and lowering the rates of glutamine metabolism and
ammonium excretion.

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Role of the lungs :

● One mechanism the body uses to control blood pH involves the release of carbon dioxide
from the lungs. Carbon dioxide, which is mildly acidic, is a waste product of the processing
(metabolism) of oxygen and nutrients (which all cells need) and, as such, is constantly produced
by cells. It then passes from the cells into the blood. The blood carries carbon dioxide to the lungs,
where it is exhaled. As carbon dioxide accumulates in the blood, the pH of the blood decreases
(acidity increases).
● The brain regulates the amount of carbon dioxide that is exhaled by controlling the speed
and depth of breathing (ventilation). The amount of carbon dioxide exhaled, and consequently the
pH of the blood, increases as breathing becomes faster and deeper. By adjusting the speed and
depth of breathing, the brain and lungs are able to regulate the blood pH minute by minute.

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