Lecture 2

Response to rise in plasma phosphate concentration

. Increased release of PTH from the parathyroid gland and FGF23 from bone both reduce phosphate reabsorption in the kidney, causing increased phosphate excretion. The 2 hormones exert offsetting influences on the production of calcitriol in the kidneys.

B. Natriuretic peptides

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); main source of both is the heart.

INTEGRATION OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM WITH OTHER MECHANISMS FOR CONTROLLING BLOOD PRESSURE AND SALT A. Dr. Clayton discussed the long-term control of blood pressure and how the Renin-Angiotensin-Aldosterone system is coordinated with other systems:

1. Cardiovascular compensation mechanisms for controlling blood pressure. 2. Renal mechanisms 3. Hypothalamic mechanisms ( thirst, ADH secretion) 4. Atrial natriuretic peptide (ANP) which is also called atrial natriuretic hormone (ANH), atrial natriuretic factor (ANF) and atriopeptin participates in control of blood pressure.

Renal Response to Volume Expansion

In response to volume expansion, sodium- and fluid-retaining mechanisms are decreased (RAAS, ADH), and the increased stretch on the cardiac right atrium releases atrial natriuretic peptide, which acts at the kidneys to decrease sodium and water retention, creating a diuresis and natriuresis, eliminating the excess fluid.

Erythropoietin

Most erythropoietin is made in the kidney so patients with chronic kidney disease can develop anemia. Some erythropoietin is made in the liver but not enough to maintain needed red blood cell number.

Norepinephrine and Epinephrine

Sympathetic tone is minimal when the volume of extracellular fluid is normal. During extreme conditions (e.g. case of severe hemorrhage) sympathetic effects more important. Norepinephrine and epinephrine released from the adrenal medulla would bind to alpha-1 adrenoceptors and cause vasoconstriction of both afferent and efferent arterioles. But afferent arterioles have more alpha-1 adrenoceptors than efferent arterioles do and thus have stronger vasoconstriction to sympathetic nerve activity. If constrict afferent arterioles there is a decrease in renal blood flow and GFR.

Relationship of RBF and GFR to renal artery pressure

a. Usually the GFR remains autoregulated (i.e. relatively constant) despite the fluctuations in arterial pressure that occur during a person's normal activities. b. RBF is usually autoregulated in parallel with GRF. c. Autoregulation fails at very high or very low arterial blood pressures. d. At extremes of blood pressure autoregulation fails and GFR and RBF vary directly with the systemic blood pressure. Hypotension can result in acute kidney injury due to the associated renal ischemia. Malignant hypertension can damage the kidney from the pathologically elevated glomerular hydrostatic pressure.

Tubuloglomerular feedback mechanism for autoregulation when there is decreased renal arterial pressure.

a. When renal arterial blood pressure falls b. GFR decreases c. Fluid flow and NaC1 in tubule fluid decrease d. Uptake of NaC1 into macula densa decreases e. Which decreases release of chemical signal constricting afferent arteriole f. So afferent arteriole dilates g. So GFR increases h. Inhibition of renin release from granular cells (by the chemical signals from the macula densa) ends. So renin release increases. i. The increase in renin causes an increase in Angiotensin II which causes vasoconstriction of the efferent arteriole. This also tends to increase the GFR.

Renal mechanisms cont...

d. Angiotensin II causes renal retention of salt and water through several mechanisms. One way is through increasing the proximal tubule transport of Na+ by increasing the activity of the Na+-H+ transporter. e. Angiotensin II also causes general vasoconstriction (and acts in the brain to increase sympathetic tone, thirst and ADH release) f. Both d and e increase arterial pressure g. Angiotensin II also increases aldosterone secretion from the adrenal cortex. h. Aldosterone increases renal reabsorption of sodium which can also raise blood pressure.

Tubuloglomerular feedback may help prevent excessive fluid losses after damage to kidney proximal tubules. If proximal tubular reabsorption is reduced (e.g. because of proximal tubular damage from heavy metals or certain drugs) there will be

excessive water and NaCl delivered to the distal tubule. Tubuloglomerular feedback will cause vasoconstriction of the afferent arteriole, lowering GFR and preventing excessive fluid loss from the damaged nephrons.

Autacoid

from the Greek auto=self, akos = remedy • Substance produced in an area that has an effect on tissue in the same area. Substance does not need to enter the circulation to have its effect.

The Glomerular Filtration Rate is the total volume of fluid that

is filtered from the plasma into the nephrons per unit time. (GFR is measured in ml/min, liters/day etc.) There are intrinsic renal mechanisms which are responsible for holding GFR and RBF relatively constant when arterial blood pressure varies within the normal range (~ 90 to 180 mm Hg).

The active form, 1,25-dehydroxy vitamin D, is a hormone.

1. 1,25-dehydroxy vitamin D is made in the kidney and travels through the bloodstream. It increases the absorption of calcium and phosphate the intestine. This is the most important effect of vitamin D /calcitriol. 2. It also stimulates renal tubule reabsorption of calcium and phosphate. 3. It suppresses PTH synthesis in the parathyroid gland. So negative feedback loop: PTH increase production of calcitriol and calcitriol suppresses production of PTH. 4. It stimulates fibroblast growth factor 23 (FGF 23) secretion by osteoblasts and osteocytes in bone.

D. Angiotensin II is both a circulating hormone and a locally produced autacoid in the kidney.

1. Angiotensin II is a vasoconstrictor in the general circulation. 2. Angiotensin II preferentially constricts the efferent arteriole under most physiological conditions. The afferent arteriole is protected from the vasoconstrictor effect by the release of vasodilators (especially nitric oxide and prostaglandins) 3. Over a certain range of vasoconstriction of mainly the efferent arteriole, GFR is increased.

B. Norepinephrine and epinephrine are vasoconstrictors

1. Both are released by the adrenal medulla (but more epinephrine than norepinephrine). The sympathetic nerves to the kidney release norepinephrine. 2. Tend to constrict both the afferent and efferent arterioles thus decreasing renal blood flow and GFR. Relative constriction of afferent and efferent arterioles depends on the amount of sympathetic activity. 3. At maximum levels of sympathetic activity afferent arteriole constriction more important and there is a large reduction in both RBF and GFR.

G. Chronic renal failure

1. Chronic renal failure; low GFR which results in decreased excretion of phosphate. So high phosphate in plasma 2. High phosphate causes elevated PTH 3. Elevated PTH causes increased bone resorption 4. Result Renal osteodystrophy 5. The increased PTH would try to activate vitamin D in kidneys but if not enough kidney cells there is decrease in vitamin D. So there is decrease in calcium absorbed from intestine. If less calcium in plasma this is also a signal to increase PTH which, as above, increases bone resorption.

E. Fibroblast growth factor 23 (FGF23)

1. FBGF 23 is a peptide hormone that is made by osteoblasts and osteocytes in bone. 2. FGF23 secretion is increased by elevated levels of phosphate. 3. Calcitriol also stimulates FGF23 secretion.

Hypertension and Renal Disease

1. Hypertension (for any reason) can cause renal damage 2. Any form of renal damage tends to cause hypertension 3. So get into bad feedback circuit. Autoregulation would help blunt this effect of increased renal artery blood pressure increasing pressure in the glomerulus.

F. FGF23 actions in the kidney

1. It decreases the reabsorption of phosphate. • Similar action to that of PTH on phosphate 2. It decreases the production of calcitriol. • Opposite effect to that of PTH which increases the production of calcitriol

Reasons for Autoregulation

1. Many activities raise or lower blood pressure so want to be able to uncouple changes in blood pressure from changes in GFR and RBF. 2. Blood pressure changes suddenly and do not want to also have constant changes in urinary excretion of fluid and solute. This would interfere in fluid and electrolyte balance. 3. Excessive blood pressure (hypertension) could cause glomerular damage.

Control of parathyroid hormone (PTH)

1. PTH essential for life for without PTH plasma calcium falls to lethal levels in a few days 2. PTH controls plasma calcium concentration. Calcium acts directly on parathyroid gland; more calcium, less PTH released, less calcium more PTH released 3. Phosphate also affects PTH secretion and chronically high levels of phosphate lead to elevated PTH

C. Endothelin is a vasoconstrictor released by damaged vascular endothelial cells

1. Plasma endothelin concentrations are increased in certain pathophysiologic conditions (e.g. toxemia of pregnancy, acute renal failure) 2. Endothelin may contribute to renal vasoconstriction and decreased GFR found in above conditions.

Glomerulotubular Balance (GT)

1. Renal tubules increase their reabsorption rate when GFR increases; this is called glomerulotubular balance. 2. Glomerulotubular balance especially prominent for Na+ and change in reabsorption occurs within seconds of change in GFR. 3. Not responsible for mechanism responsible for GT. (See Vander's Renal Physiology 8th ed. p119 if interested.) 4. Autoregulatory mechanisms discussed above and glomerulotubular balance both would help to decrease changes in urinary output with changes in blood pressure. 5. Despite these mechanisms increases in arterial blood pressure still have an effect on the excretion of water and sodium (pressure diuresis or pressure natriuresis).

D. PTH actions

1. Stimulates final activation of vitamin D in the kidney i.e. production of calcitriol. 2. PTH increases renal-tubular calcium reabsorption 3. PTH reduces proximal tubular reabsorption of phosphate. So increases urinary phosphate excretion and decreases extracellular phosphate concentration 4. Complicated effect on bone, normally increases the movement of calcium from bone into extracellular fluid.

Production of the active form of vitamin D

1. Vitamin D (in diet) actually prohormone that has to undergo two hydroxylation reactions to become the active form 2. Pathway to active form of vitamin D can also start in skin where light can cause formation of vitamin D3 3. Vitamin D3 (cholecalciferol) is converted in the liver to 25-hydroycholecaliferol 4. This converted in the kidney to 1,25-dihydroxy vitamin D also called calcitriol. 5. The final hydroxylation step in the kidney is stimulated by parathyroid hormone (PTH).

Angiotensin II is both a circulating hormone and a locally produced autacoid in the kidney. cont...

4. Decreased arterial pressure or decreased blood volume tend to cause an increase in Angiotensin II. These same conditions would tend to decrease glomerular pressure and GFR. So the increased Angiotensin II tends to prevent the fall in GFR that would otherwise occur. (Guyton and Hall 12th ed. p 318) 5. Angiotensin II has a very short half-life (< 1 minute) while renin and aldosterone have longer but still short plasma half-lives (~ 15 minutes) (Vander's Renal Physiology 8th ed. P 114). This helps the body to keep tight control on the rate of water and sodium reabsorption in the kidney.

Angiotensin II

Angiotensin II constricts arterioles throughout the body. In the kidney it has a greater affect on the efferent arterioles than on the afferent arterioles so it tends to maintain the GFR despite the decrease in renal blood flow due to constriction of the afferent arteriole. If a patient is dependent on above to maintain GFR then giving ACE inhibitor may cause problems.

Alterations in the erythropoietin feedback circuit.

Any factor decreasing oxygen delivery to the oxygen sensor cells results in increased secretion of erythropoietin and a compensatory increase in erythrocyte production as illustrated in A for anemia, with a decrease in erythrocyte mass, and in B for hypoxia, with a decrease in arterial oxygen saturation. An increase in erythrocyte mass, as occurs with polycythemia vera (C), decreases erythropoietin production.

Vasodilator Prostaglandins

As you learned in earlier lectures normal endothelial cells make prostacyclin which is a vasodilator. In the kidneys the vasodilator prostaglandins can oppose the vasoconstricting action of vasoconstrictors like norepinephrine. Drugs that inhibit prostaglandin synthesis can cause ischemic renal damage in some patients.

Responses to reduced plasma calcium concentration.

Reduced plasma calcium stimulates secretion of PTH. Bone immediately releases calcium from the labile pool into the ECF both stimulated by PTH and independently. PTH also stimulates renal calcium reabsorption and reduces phosphate reabsorption, thereby lowering plasma phosphate and preventing formation of calcium phosphate complexes. On a slower time scale, PTH stimulates osteoclastic bone resorption and increased synthesis of calcitriol from vitamin D in the kidney, leading to increased calcium absorption from the GI tract.

Chronic Renal Disease

When a patient has lost nephrons through injury or disease their kidneys can compensate by increasing the filtration through each of their remaining nephrons. If the increase in GFR is dependent on increased vasodilator prostaglandins, then taking N-SAIDS may precipitate immediate renal failure

Tubuloglomerular feedback mechanism for autoregulation when there is increased renal arterial pressure

a. If renal arterial pressure is increased, this would increase RBF and GFR. So need a feedback mechanism to decrease RBF and GFR. b. If you constricted the afferent arterioles this would decrease RBF and GFR. So what is mechanism that causes an increase in renal arterial pressure to cause vasoconstriction of the afferent arteriole? c. Increased renal arterial pressure causes • Increased GFR and RBF; this causes... • Increased flow rate through proximal tubule • Since flow quicker, less time to absorb water and NaC1 in proximal tubule so larger than normal volume of tubular fluid reaches loop of Henle per unit time (Glomerulotubular balance means that percentage of water and most solutes reabsorbed in proximal tubule still ~ 65%.) • Larger than normal volume of tubular fluid reaches distal loop of Henle. • Macula densa senses increased flow via cilia that project into the tubular lumen from macula densa cells. It also senses sodium chloride. • Probably chemical signals from macula densa cells (in response to flow and NaCl) diffuse to nearby smooth muscle cells of afferent arteriole and cause vasoconstriction of afferent arteriole. A probable mediator is adenosine. Although in many vessels adenosine causes vasodilation, it causes vasoconstriction of the afferent arterioles of the kidney.

Vasodilator Prostaglandins 2. Chronic Renal Disease

a. If the number of nephrons is decreased, the kidneys compensate by increasing the filtration of each nephron-increase in single nephron GFR. b. This adaptation can be maintained by increasing PGE2 and PGI2 thus dilating afferent arterioles and increasing single nephron GFR. c. If patient with chronic renal disease takes N-SAIDS which decrease the vasodilating prostaglandins, this may precipitate immediate renal failure.

Hypothalamic mechanisms ( thirst, ADH secretion):

a. Increase in blood osmolality causes thirst. Angiotensin II also causes thirst. Thirst causes intake of water. A large blood loss which decreases blood volume can also cause thirst. b. Increase in blood osmolality or decrease in blood volume causes increased release of ADH. c. The increase in ADH caused by a large blood loss is higher than that needed for maximal water reabsorption and urine concentration. The large concentration of ADH has a direct vasoconstrictor effect on both general circulation and renal arterioles. (Remember that the other name for ADH is vasopressin.) General vasoconstriction would help to raise the blood pressure which had been lowered by blood loss. The vasoconstriction of renal arterioles lowers GFR and thus helps retain salt and water.

Myogenic mechanism

a. Individual blood vessels can resist stretching during increased arterial pressure. Thought that most arterioles in the body respond to increased wall tension by contraction of vascular smooth muscle. So the rise in pressure in the afferent arteriole of the glomerulus causes the arteriole to vasoconstrict. This would raise vascular resistance and decrease the rise in glomerular hydrostatic pressure that would otherwise occur from the increase in systemic blood pressure. This helps prevent excessive increases in RBF and GRF when arterial pressure increases. b. By preventing excessive glomerular hydrostatic pressure myogenic mechanism minimizes damage to glomerular capillaries. c. When the pressure in the afferent arteriole falls there is reflexive vasodilation of the afferent arteriole thus maintaining/increasing GFR and RBF

Renal mechanisms

a. Kidney releases renin in response to low blood pressure (direct effect on renal baroreceptor cells) and in response to sympathetic stimulation of β1 adrenergic receptors on granular cells/renal barorecptors b. Renin breaks angiotensinogen (from liver) down into Angiotensin I c. ACE, Angiotensin converting enzyme converts angiotensin I into angiotensin II

Vasodilator Prostaglandins 3. Most of renal blood flow is to the cortex but medullary blood flow tends to be especially dependent on vasodilatory prostaglandins.

a. Medullary ischemic injury is often first sign of injury resulting from overdose of N-SAIDS b. Juxtamedullary nephrons (whose loops of Henle extend into the medulla) are necessary for establishing a strong osmotic gradient. So loss of ability to concentrate urine is often first sign of N-SAID abuse

Vasodilator Prostaglandins 1. PGE2 and PGI2 (prostacyclin)

a. Normally just small amount these prostaglandins produced but synthesis increased by the vasoconstrictor hormones angiotensin II, norepinephrine and vasopressin. These prostaglandins oppose the actions of vasoconstrictors. So when for example, sympathetic tone is increased and norepinephrine is released onto afferent and efferent arterioles there is less vasoconstriction (then would occur if the prostaglandins were not present). b. If you reduce the amount of PGE2 and PGI2 synthesized unopposed vasoconstriction might cause renal damage. c. The nonsteroidal anti-inflammatory drugs (N-SAIDS) such as aspirin, ibuprofen and naproxen inhibit prostaglandin synthesis and can cause ischemic renal damage in some patients. d. Inhibition of prostaglandin synthesis can also cause significant decreases in GFR under stressful conditions that increase sympathetic activity.

2. Actions of natriuretic peptides;

a. Relax afferent arteriole and so increase GFR b. Inhibit release of renin c. Inhibit/decrease Angiotensin II actions that normally promote the reabsorption of sodium d. Inhibit sodium absorption in the medullary collecting duct e. Reduces aldosterone secretion from the adrenal cortex f. Result is that ANP stimulates the excretion of sodium. Increased sodium excretion causes increased water loss from the body, so decreased plasma volume, decreased blood pressure.