Functions of the urinary system Excretion The removal of organic waste products from body fluids Elimination The discharge of waste products into the environment Homeostatic regulation of blood plasma Regulating blood volume and pressure Regulating plasma ion concentrations Stabilizing blood pH Conserving nutrients

Tubular Functions Renal Clearance Studies 1. General: Powerful, relatively non-invasive, technique through which a great deal of renal function can be studied.

Figure 26.3 The Urinary System in Gross Dissection

Figure 26.4 The Structure of the Kidney Figure 26.4a, b

Figure 26.5 The Blood Supply to the Kidneys Figure 26.5a, b

Figure 26.6 A Representative Nephron

Nephron functions include: Production of filtrate Reabsorption of organic nutrients Reabsorption of water and ions Secretion of waste products into tubular fluid

Two types of nephron Cortical nephrons ~85% of all nephrons Located in the cortex Juxtamedullary nephrons Closer to renal medulla Loops of Henle extend deep into renal pyramids

Figure 26.7 Cortical and Juxtamedullary Nephrons Figure 26.7a

Figure 26.7 Cortical and Juxtamedullary Nephrons Figure 26.7b, c

Figure 26.9 An Overview of Urine Formation

Urine production maintains homeostasis Regulating blood volume and composition Excreting waste products Urea Creatinine Uric acid

Basic processes of urine formation Filtration Blood pressure Water and solutes across glomerular capillaries Reabsorption The removal of water and solutes from the filtrate Secretion Transport of solutes from the peritubular fluid into the tubular fluid

Functional anatomy of the nephron Proximal convoluted tubule (PCT) Actively reabsorbs nutrients, plasma proteins and ions from filtrate Released into peritubular fluid Loop of Henle Descending limb Ascending limb Each limb has a thick and thin section

Functional anatomy of the nephron Distal convoluted tubule (DCT) Actively secretes ions, toxins, drugs Reabsorbs sodium ions from tubular fluid

Figure 26.8 The Renal Corpuscle Figure 26.8a, b

Figure 26.8 The Renal Corpuscle Figure 26.8c, d

Figure 26.10 Glomerular Filtration Figure 26.10a, b

Glomerular filtration rate (GFR) Amount of filtrate produced in the kidneys each minute Factors that alter filtration pressure change GFR

Figure 26.11 The Response to a Reduction in the GFR Figure 26.11a

Reabsorption and secretion at the PCT Glomerular filtration produces fluid similar to plasma without proteins The PCT reabsorbs 60-70% of the filtrate produced Reabsorption of most organic nutrients Active and passive reabsorption of sodium and other ions Reabsorption of water Secretion also occurs in the PCT

Figure 26.12 Transport Activities at the PCT

CA = carbonic anhydrase THE TRANSPORTERS Glomerular Filtrate (plasma-like) Proximal Tubule Reabsorbs: high in Na+, Cl-, HCO3-, glucose, etc. Na+, Cl-, HCO3-, H2O, glucose, amino acids, and more Cl- Cl- 3 4 Na/H HCO3- + H+ H+ + HCO3- CO2 + H2O CA Na+ HCO3- CO2 + H2O 5 CA R. 380 CA = carbonic anhydrase

Review of Renal Tubular mechanisms for H+ secretion & excretion Reabsorption of filtered HCO3-: predominantly in proximal tubule conservation reabsorption of filtered HCO3 + H2O CA (brush border) CA

H+ H+ secretion H+ excretion ATP ATP new HCO3- absorbed in urine Some Transporters Apical Na+/H+ exchanger Apical H+-ATPase (ATP-dep. pump) Apical H+/K+-ATPase (pump) Apical Na+/NH4+ exchanger Basolateral Na+-HCO3- co-transporter HPO42- Cl- Ex Co HCO3- H+ secretion Cl- Na+ H+ Ex HCl HPO42- K+ H+ ATP H+ Co H+ H2PO4- ATP new HCO3- absorbed H+ excretion Ex Co in urine

acidosis alkalosis

Respiratory and Renal Compensatory Mechanisms for ACID-BASE Disturbance

Summary of Principal Proximal Tubular Transport Mechanisms Na+-coupled co-transporters Na+-H+ exchanger Apical membrane Basolateral membrane also there are water channels (Aquaporins) in the apical and basolateral membranes Na+ 3 1 (other stoichiometry possible, e.g., 2:1)

The loop of Henle and countercurrent multiplication Between ascending and descending limbs of loop Creates osmotic gradient in medulla Facilitates reabsorption of water and solutes before the DCT Permits passive reabsorption of water from tubular fluid

Function of the vasa recta Removes solutes and water Balances solute reabsorption and osmosis in the medulla

Figure 26.13 Countercurrent Multiplication and Concentration of Urine Figure 26.13b

Figure 26.13 Countercurrent Multiplication and Concentration of Urine

Figure 26.13 Countercurrent Multiplication and Concentration of Urine Figure 26.13a

Reabsorption and secretion at the DCT DCT performs final adjustment of urine Active secretion or absorption Absorption Tubular cells actively resorb Na+ and Cl- In exchange for potassium or hydrogen ions (secreted)

Figure 26.14 Tubular Secretion and Solute Reabsorption at the DCT

Figure 26.14 Tubular Secretion and Solute Reabsorption at the DCT Figure 26.14c

Reabsorption and secretion along the collecting system Water and solute loss is regulated by aldosterone and ADH Reabsorption Sodium ion, bicarbonate, and urea are resorbed Secretion pH is controlled by secretion of hydrogen or bicarbonate ions

Figure 26.16 A Summary of Renal Function

Figure 26.11 The Response to a Reduction in the GFR Figure 26.11b

Sympathetic activation Produces powerful vasoconstriction of afferent arterioles Decreases GFR and slows production of filtrate Changes the regional pattern of blood flow Alters GFR Stimulates release of renin by JGA

Hypothalamus, posterior pituitary and ADH secretion– connection with baroreceptors

Synthesis of ADH It is synthesized as pre-prohormone and processed into a nonapeptide (nine amino acids). Six of the amino acids form a ring structure, joined by disulfide bonds. It is very similar in structure to oxytocin, differing only in amino acid #3 and #8. ADH synthesized in the cell bodies of hypothalamic neurons in the supraoptic nucleus ADH is stored in the neurohypophysis (posterior pituitary)—forms the most readily released ADH pool

Hypothalamus and posterior pituitary

Structure of ADH

Synthesis of ADH Mechanical disruption or the neurohypohyseal tract by trauma, tumor, or surgery temporarily causes ADH deficiency. ADH will be restored after regeneration of the axons (about 2 weeks). But if disruption happens at a high enough level, the cell bodies die in the hypothalamus resulting in permanent ADH deficiency

Primary action of ADH: antidiuresis ADH binds to V2 receptors on the peritubular (serosal) surface of cells of the distal convoluted tubules and medullary collecting ducts. Via adenylate cyclase/cAMP induces production and insertion of AQUAPORIN into the luminal membrane and enhances permeability of cell to water. Increased membrane permeability to water permits back diffusion of solute-free water, resulting in increased urine osmolality (concentrates urine).

ADH increases renal tubular absorption of water

Figure 26.15 The Effects of ADH on the DCT and Collecting Ducts Figure 26.15a, b

ADH and blood pressure

ADH and plasma osmolality

Pathway by which ADH secretion is lowered and water excretion raised when excess water is ingested

Pathway by which ADH secretion and tubular permeability to water is increased when plasma volume decreases

Aldosterone synthesis Aldosterone is synthesized and secreted by the zona glomerulosa . The synthesis of aldosterone from cholesterol to corticosterone is identical to the synthesis of glucocorticoids in the zona fasiculata. The C18 methyl group of corticosterone is hydroxylated and converted to an aldehyde yielding aldosterone.

Aldosterone synthesis in the adrenal zona glomerulosa

Aldosterone function The principal function of aldosterone is to sustain extracellular fluid volume by conserving body sodium. Aldosterone is largely secreted in response to signals that arise from the kidney when a reduction in circulating fluid volume is sensed. When body sodium is depleted, the fall in extracellular fluid and plasma volume decreases renal arterial blood flow and pressure.

The kidney is the major site of mineralocorticoid activity. Aldosterone action Aldosterone binds to the mineralocorticoid receptor in target cells and affects transcriptional changes typical of steroid hormone action. The kidney is the major site of mineralocorticoid activity.

Increased blood pressure results from excess aldosterone. Aldosterone action Increased blood pressure results from excess aldosterone. Hypertension is an indirect consequence of sodium retention and expansion of extracellular fluid volume.

Aldosterone action Aldosterone stimulates the active secretion of potassium from the tubular cell into the urine. Most potassium that is excreted daily results from distal tubular secretion. Hence aldosterone is critical for disposal of daily dietary potassium load at normal plasma potassium concentrations.

Regulation of aldosterone secretion: Activation of renin-angiotensin system in response to hypovolemia is predominant stimulus for aldosterone synthesis.

Pathway by which aldosterone secretion and tubular sodium reabsorption is increased when plasma volume is decreased

Pathway by which an increased potassium intake induces greater potassium excretion mediated by aldosterone

Aldosterone Angiotensin II acts on the zona glomerulosa to stimulate aldosterone synthesis. Angiotensin II acts via increased intracellular cAMP to stimulate aldosterone synthesis.

Aldosterone mechanism The aldosterone-induced proteins serum and glucocorticoid-inducible kinase (Sgk), corticosteroid hormone-induced factor (CHIF), and Kirsten Ras (Ki-Ras) increase the activity and/or no. of these transport proteins during the early phase of action

Aldosterone Action

Aldosterone time course of action

Action of aldosterone on the renal tubule Action of aldosterone on the renal tubule. Sodium reabsorption from tubular urine into the tubular cells is stimulated. At the same time, potassium secretion from the tubular cell into urine is increased. Na+/K+-ATPase, and Na+ channels work together to increase volume and pressure, and decrease K+.

Horacio J. Andorgué & Nicolaos E. Midias

Cortisol is at 1000 fold higher concentrations than aldosterone