Define tubular reabsorption, Identify and describe tubular secretion, Describe tubular secretion mechanism involved in transcellular and paracellular with PAH transport and K+ Glucose reabsorption transport.

Identify and describe Identify and describe the Study glucose titration curve mechanisms of tubular characteristic of loop of in terms of renal threshold, transport & Henle, distal convoluted tubular transport maximum, Describe tubular reabsorption tubule and collecting ducts splay, excretion and filtration of sodium and water for reabsorption and secretion

Identify the tubular site and Identify the site and describe Revise tubule-glomerular describe how Amino Acids, the influence of aldosterone feedback and describe its HCO -, P0 - and Urea are on reabsorption of Na+ in the physiological importance 3 4 reabsorbed late distal tubules.

Mind Map As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive parts of the tubule: The proximal tubule → the loop of Henle(1) → the distal tubule(2) → the collecting tubule → finally ,the collecting duct, before it is excreted as urine.

A long this course, some substances are selectively reabsorbed from the tubules back into the blood, whereas others are secreted from the blood into the tubular lumen.

The urine represent the sum of three basic renal processes: glomerular filtration, tubular reabsorption, and tubular secretion:

Urinary excretion = Glomerular Filtration – Tubular reabsorption + Tubular secretion

Mechanisms of cellular transport in the nephron are:

Active transport Pinocytosis\ Passive Transport Osmosis “Active transport can move a solute exocytosis against an electrochemical gradient and requires energy derived from metabolism” Water is always reabsorbed by a Simple diffusion passive (nonactive) (Additional reading) Primary active (without carrier physical mechanism Secondary active The proximal tubule, reabsorb protein) called osmosis , transport large molecules such as transport Cl, HCO3-, urea , which means water proteins by pinocytosis. In this diffusion from a region Transport that is Transport that is creatinine process, the protein attaches to coupled directly to of low solute the brush border of the luminal coupled indirectly to an concentration (high membrane, then invaginates to an energy source energy source due to the interior of the cell until it is such as ATP water concentration) to completely pinched off and a concentration gradient vesicle is formed containing the of ion one of high solute protein. Once inside the cell Facilitated Sodium-potassium concentration (low the protein is digested into its diffusion water concentration). constituent amino acids, which pump are reabsorbed through the Na-K-2Cl co-transport (require carrier basolateral membrane into the protein) interstitial fluid. Because (found in basolateral pinocytosis requires energy, it is membrane along renal glucose-sodium co- Glucose and amino considered a form of active tubules) transport (SGLT) acids at the transport. basalateral border (GLUT) amino acid-sodium co- transport (1) Co-transport : movement of two molecules in the same direction but they opposite in concentration gradient H+-pump H+/Na counter-

transport (2) Counter-transport: movement of two molecules in opposite direction based on their concentration gradient The ways of transport: 1- From lumen of tubules (Apical membrane”1”) to epithelial cells Second, through the First, Reabsorption of then from epithelial cells to interstitium (Basolateral membrane): renal interstitium , and filtered water and solutes A-Transcellular route: (through the cell membrane) back into the blood from the tubular lumen B-Paracellular route: (between spaces of tight cell junction) through the Peritubular across the tubular capillary membrane epithelial cells

2- From interstitium (basolateral space) to the Peritubular capillaries: By ultrafiltration (bulk flow) that is mediated by: hydrostatic and colloid osmotic forces

(1) Apical membrane = brush border which is numerous to help in reabsorbation 1. : A. Sodium diffuses across the luminal membrane (also called the apical membrane) into the cell down an electrochemical gradient (with other substances such as glucose, amino acids etc.) established by the sodium -potassium ATPase pump on the basolateral side of the membrane. B. Other molecules like water and Cl , Ca etc. by osmosis and diffusion

2. : A. Sodium is transported across the basolateral membrane against an electrochemical gradient by the sodium -potassium ATPase pump B. other substances will across the basolateral membrane by passive diffusion

3. Sodium , water , and other substances are reabsorbed from the interstitial fluid into the Peritubular capillaries by ultrafiltration (bulk flow ”1”), a passive process driven by the hydrostatic and colloid (1) Bulk flow = movement of water with other substances osmotic pressure gradients While diffusion = movement of substances without water. In Peritubular capillaries the high plasma oncotic pressure is due to fluid filtration in glomerulus increase GFR  increase oncotic pressure & decrease hydrostatic pressure in efferent & Peritubular capillaries  increase bulk flow from lateral space to Peritubular capillaries  increse reabsorption decrease GFR  decrease oncotic pressure & increase hydrostatic pressure  decrease bulk flow  fluid go back to lumen through tight junction  decrease reabsorption

1- Responsible for producing a concentrated urine in the medulla.

2- When ADH (antidiuretic hormone) is 1- Proximal tubules is coarse adjustment present, water is reabsorbed and urine is (reabsorption a most of of water and concentrated. solutes) Descending limb: (concentrate urine ”1”) 3-100% of glucose and amino acids 1- water permeable and allow reabsorbed absorption of 25% of filtered H2O. 2-It is impermeable to Na-CL. 2- Solute reabsorption in the proximal 3-fluid become hyper-osmolar

tubule is isosmotic (equal amount of Thin ascending limb: (dilute urine ”2”) solute and water are reabsorbed) 1- impermeable to H2O

2- permeable to NaCl (passive) 3-By the end of ascending limb of loop, (1) Concentrate urine = remove water from fluid the tubular fluid becomes hypo-osmolar

(2) Dilute urine = remove solutes from urine Thick ascending limb: (dilute urine) 1- impermeable to H2O * The main function of tubules is concentrate urine 2- Na-K-2Cl co-transport occur in this and that has done in loop of henle of Juxtamedullary nephron part. (active) 3-the tubular fluid becomes hypo- * Sodium-potassium pump that found in osmolar to plasma in this part distal convoluted tubules is under control of aldosterone

1- Distal tubule is fine adjustment

(reabsorption a fine amount of water and solutes by 1- Composed of two types of cells: hormonal control based on body needs) a. Principal cells: absorb Na+& H2O and secrete K+

b. Intercalated cells: absorb K+ & secrete H+ 2- The first portion of DCT forms part of Juxtaglomerular Apparatus, that provides feedback •Secretion of K+ and reabsorption of Na+ controlled control of GFR and RBF of the same nephron. by aldosterone.

2- water permeability under ADH control. (works 3-The next early portion has the same characteristics under body needs) as ascending limb of Henle that is 1-impermeable to water 3- Impermeable to Urea.

2-absorbs solutes. So it is called the diluting segment & the osmotic pressure of the fluid ~ 100 mOsm/L.

1- Under ADH control. (works under body needs) 2- Highly permeable to urea. 3- Final site for processing urine. 4- Secretes H+ helps to: a- maintain blood pH b- reabsorb HCO3 and generate new HCO3 Reabsorbation Secretion

- Poorly reabsorbed of creatinine and urea - 60% - 75% of sodium and water - H+ Proximal convoluted tubules - 90% of HCO3, K+, Ca and Cl- - Urea - 100% Glucose and amino acids - ammonia

Descending loop of henle -25% of water (H2O) ______

Thin ascending loop of henle - Sodium chloride (NaCl) ______

- Sodium Thick ascending loop of henle - Potassium ______- Chloride

- Sodium in response to aldosterone - Potassium in response of aldosterone Distal convoluted tubules - Water in response of ADH

- Calcium in response of parathyroid hormone

a. Principal cells: absorb Sodium Na+ & H2O Late distal tubule & Cortical b. Intercalated cells: absorb Potassium K+ & HCO3 a. Principal cells: secert K+ -Water in response of ADH b. Intercalated cells: secret H+ Collecting ducts - Sodium in response to aldosterone Potassium in response of aldosterone - Calcium in response of parathyroid hormone

-Water in response of ADH Medullary Collecting ducts - Highly permeable to urea ( to maintain osmolarity of - H+ medulla )

Site Between Functions

Primary Active Transport

Sodium-potassium Reabsorbation of sodium and secrete potassium to maintain All renal tubules Basolateral membrane pump the intracellular and extracellular balance of Na and K Secondary Active Transport

H+/Na counter- Proximal convoluted tubules, Distal Reabsorbation of sodium and secrete hydrogen ion and It is Apical membrane transport convoluted tubules and collecting ducts coupled with bicarbonate transport Proximal convoluted tubules, Late HCO3/Na co-transport distal convoluted tubules and collecting Basolateral membrane Reabsorbation of sodium and bicarbonate ducts Reabsorbation of sodium, potassium and two chloride to Na-K-2Cl co-transport Thick ascending limb of henle’s loop Apical membrane dilute water glucose-sodium co- Proximal convoluted tubules Apical membrane Reabsorbation of sodium and glucose transport (SGLT) Amino acid-sodium co- Proximal convoluted tubules Apical membrane Reabsorbation of sodium and amino acid transport Simple diffusion Passive NaCl transport Thin ascending limb of henle’s loop Apical membrane Reabsorbation of NaCl to dilute fluid in tubules

Passive channels of K+ , Apical membrane & All renal tubules Reabsorbation and secretion Cl , Ca etc. Basolateral membrane Facilitated diffusion Glucose transporter Proximal convoluted tubules Basolateral membrane Reabsorbation of glucose to interstitial fluid (GLUT) Osmosis All renal tubules except: Apical membrane & Water 1- thin and thick ascending limp and Reabsorbation of water Basolateral membrane 2- early portion of distal convoluted tubules • Essentially all glucose is reabsorbed

• The renal threshold for glucose= 180 mg/dl • Glucose inter the tubular cells by secondary active transport

“co-transport”, It use SGLT “a specific transport protein • the tubular transport maximum for glucose “which needs Na” . Tmg = 375 mg/min in men and 300 mg/min in

women. • Then it’s cross the cell membrane into the interstitial spaces by facilitated transport “passive transport” which use GLUT’s “do not need Na” .

• Glucose reabsorption occur in proximal tubule . What is the difference between renal threshold and tubular transport maximum ?

Renal threshold : it’s the rate that glucose begins What cause the excretion of glucose in urine to appear in the urine . before reach to its maximum transport? transport maximum for glucose : all nephrons have reached their maximal capacity to reabsorb glucose “maximum saturation of transporters” not all nephrons have the same transport maximum for glucose, and some of the nephrons therefore begin to excrete glucose before others have reached their transport maximum - • First of all, bicarbonate (HCO3 ) attaches itself + with hydrogen (H ) then it becomes H2CO3 in 1 the lumen

• Carbonic Anhydrase will break H2CO3 down to water (H2O) + carbonic dioxide (CO2) which 2 diffuses into the proximal tubule

• Carbonic Anhydrase will convert the water - + 3 (H2O) + the carbon dioxide (CO2) to HCO3 + H

• Hydrogen will transport out and sodium (Na) 4 will come in the proximal tubule

• Lastly, the HCO - will go into the blood 5 3 Relations among the filtered load of glucose, the rate of glucose reabsorption by the renal tubules, and the rate of glucose excretion in the urine There must be a balance between tubular reabsorption and glomerular filtration. This is controlled by local , nervous & hormonal mechanisms.

1.Glomerulotubular balance: prevents overloading of 5-Tubuloglomerular feedback: it will observe distal parts when GFR increases. concentration of sodium chloride by macula dense in distal tubules and what will lead to: 1- constriction and dilatation of afferent arteriole which affect on GFR 2. Peritubular capillary reabsorption is regulated by 2- release renin which increase reabsorabtion of sodium hydrostatic and colloidal pressures through the and play a role in production of angiotensin II capillaries.

6-Hormonal: - Angiotensin II : release aldosterone 3. Arterial blood pressure: if increased it reduces - ADH : H2O reabsorbation tubular reabsorption. (increase in blood pressure will reduced GFR in response of myogenic mechanism and - ANP : Sodium excretion and diuresis the decrease reabsorbation) Parathyroid hormone: Increases Ca reabsorption & decreases phosphate reabsorption

4. Nervous Sympathetic: (1) ADH: Antidiuretic hormone -Increases Na+ reabsorption. (2) ANP: atrial nitric peptide (3) Diuresis: increase urine output Function • 1-increases Sodium reabsorption • 2-stimulates Potassium secretion When does it secreted? • (1) Increased extracellular potassium concentration. • (2) Increased angiotensin II levels, which typically occur in conditions associated with sodium and volume depletion or low blood pressure (so it will increase blood pressure) Site of secretion • Aldosterone, secreted by the zona glomerulosa cells of the adrenal cortex. Mechanism of action • by stimulating the sodium-potassium ATPase pump on the basolateral side of the cortical collecting tubule membrane. • Aldosterone also increases the sodium permeability of the luminal side of the membrane . Diseases associated with aldosterone • Absence of aldosterone, as occurs with adrenal destruction or malfunction (Addison’s disease) • Excess aldosterone, as occurs in patients with adrenal tumors (Conn’s syndrome) is associated with: 1- sodium retention 2- decreased plasma potassium concentration

• Absorption throw apical Proximal tubules: membrane is done 1- has the greatest passively. effect in all tubules. Distal tubules: • Movement of Na throw 2- the fluid inside it is 1- Has mucla densa which isosmotic. is Na sensitive + excretes basal membrane is done renin. Na/K ATPase. 2- has principal cell: Na + H2o absorption & K • ↑ GFR → ↑ Absorption secretion 3- has intercalated cell: absorbs K and secretes H+ • Sympathetic → ↑ Na (controls pH) Loop of Hele: absorption * Descending: concentrate urine by reabsorption of water. * Thin ascending: Absorbed Na • ADH → ↑ H2O absorption Cl * Thick ascending: Absorbed Na 2Cl K • Aldosterone → ↑ Na absorption + K excretion

• ANP ↑ Na excretion

Ans Q1: One of these examples is control passively: Q5: Most of filtered water is reabsorbed in:

A/Transport maximum A/ Proximal convoluted tubule (PCT) : 1

B/Transcellular reabsorption B/Distal convoluted tubule (DCT) - C/Paracellular reabsorption C/Ascending loop of henle C,

D/co-transport D/Descending loop of henle 2 -

B,

Q2: where is Sodium-potassium specific pumps? Q6: Glucose reabsorption is the difference between: 3

A/Basement membrane A/the amount of glucose filtered and the amount Secreted - D, B/Basolateral membrane B/the amount of glucose filtered and the amount excreted.

C/Interstitial wall C/the amount of glucose reabsorbed and the amount excreted. 4 - D/Cytoplasmic membrane D/the amount of glucose reabsorbed and the amount secreted C,

5 -

Q3: Where can you found sodium-potassium pump? In Q7: When plasma glucose reach which called “glucose renal A,

between.. threshold” , How much is glucose level in vein that will lead to 6

A/Tubular lumen & tubular cell. appear in urine ? - B/Iinterstitial fluid & tubular lumen. A/250mg/dl B,

C/ interstitial fluid, tubular cell & tubular lumen. B/375 mg/dl 7 -

D/interstitial fluid & tubular cell C/180mg/dl C.

D/200mg/dl 8

Q4: When 3 Na / 2 K pumped in Basolateral - A, A, membrane, the net result is: Q8: How much is maximum absorptive capacity for glucose in A/High intracellular Na concentration men? B/Low Extracellular Na concentration A/375mg/min C/ osmolarity in the basolateral space B/200mg/dl D/osmolarity in the basolateral space. C/250mg/min D/300mg/min

Ans Q9: Amino acid is reabsorbed in Basolateral membrane by : Q13: Which of the following is an site of NaCl

A/ATP diffuses passively ? : A/Proximal convoluted tubule (PCT). 9

B/ Diffusion - C/ Co-transport with Na B/ thin ascending loop. B,

D/Na+/K+ ATPase C/ Distal convoluted tubule (DCT ). 10 D/ thick ascending limb .

-

Q10: What is the main important mechanism for Na B , , exchange on Bicarbonate reabsorption ? Q14: the amount of water, solute reabsorption and 11 A/Reabsorpetion of HCO secretion depends on : 3 - B/Secreted H+ A/Age D,

C/Diffuses CO2 B/Wight 12 D/Filtered HCO C/ body’s needs

3 - D/secrete H+ D,

Q11: At the end of descending loop of henle the osmolarity 13

will be : Q15: During Reabsorption/secretion of H2O in Late -

A/Decrease Distal Tubules and Collecting Tubules, the H2O is B, more dependent on : B/No change 14

C/Minimal change A/Angiotensin II -

D/Increase B/principal cells C, C/Aldosterone

15

Q12: Which site has a high permeability of water: D/Anti-Diuretic hormone -

A/Thick ascending loop of henle D.

B/Thin ascending loop of henle

C/Early portion of Distal convoluted tubule D/Thin descending loop of henle