Renal System II: Regulation Lecture Notes
Renal System II: Regulation
Overview of Renal Physiology
Key Components:
2 K+ and 3 Na+ ATP dynamics involved in renal function, primarily through the Na^+/K^+ ATPase pump.
Learning Objectives of Renal System II
A. Understanding Clearance
Recognize why inulin is a reliable measure for determining Glomerular Filtration Rate (GFR) due to its properties of being freely filtered and neither reabsorbed nor secreted.
B. Renal Clearance of Glucose
The renal clearance of glucose is typically zero in healthy individuals, reflecting complete reabsorption. However, this can be altered in individuals with diabetes mellitus, under conditions of hyperglycemia, leading to glucosuria.
C. Clearance of Penicillin
Renal clearance of penicillin surpasses GFR due to active secretion mechanisms in the proximal tubule.
D. Regulation of Water Reabsorption by Vasopressin
Differentiate between diabetes insipidus, characterized by an inability to concentrate urine due to either lack of vasopressin production (central) or lack of vasopressin receptors (nephrogenic), and diabetes mellitus, characterized by excess sugar in the blood leading to osmotic diuresis.
E. RAAS and Blood Pressure Regulation
Explain the functioning of the Renin-Angiotensin-Aldosterone System (RAAS) in maintaining blood pressure and fluid balance through vasoconstriction, aldosterone release, and vasopressin effects.
F. Role of Atrial Natriuretic Peptides (ANPs)
Describe how ANPs help in lowering blood pressure via natriuresis (Na+ excretion) and diuresis (water excretion) mechanisms, primarily by increasing GFR and inhibiting renin.
Functions of the Nephron
Primary Functions:
Filtration
Reabsorption
Secretion
Excretion
Renal Excretion and Clearance
Renal Excretion:
Definition: The process of removing substances from the body in urine.
Formula: Excretion = Filtration - Reabsorption + Secretion.
Measurement: Expressed as mass/time (e.g., mg/min or mg/hour).
Renal Clearance:
Definition: Measurement of the kidney’s ability to clear substances from plasma, indicated by volume/time (e.g., mL/min or mL/hour). It represents the volume of blood plasma completely cleared of a substance per unit time. This is a conceptual rate, not referring to urine volume.
Other Organs: Clearance rates can also be determined for other organs, such as hepatic clearance for the liver.
Importance of Clearance:
Provides insights into kidney function and health and can be used to determine GFR.
Ideal Substance for Clearance Measurement:
A theoretical ideal substance for clearance is freely filtered and neither reabsorbed nor secreted.
Inulin as a Benchmark for GFR
Properties of Inulin:
Inulin is utilized as a benchmark due to its ideal properties: it is a plant carbohydrate, hydrophilic, freely filtered, and neither reabsorbed nor secreted in the nephron, as there are no carrier or transporter proteins for it.
It is distinct from insulin (a protein hormone).
Experimental Determination of Clearance using Inulin:
Conceptual Understanding: If a substance like inulin is freely filtered and neither reabsorbed nor secreted, then the amount filtered equals the amount excreted. In this scenario, its clearance equals GFR.
Example: If 100 mL of plasma is filtered at a GFR of 100 mL/min, and 4 inulin molecules are present, all 4 molecules will be excreted, and the inulin clearance will be 100 mL/min, directly measuring GFR.
Clinical Use Drawback: Inulin is not widely used clinically due to the inconvenience of requiring intravenous injection.
Glucose and Urea as Examples of Clearance
Glucose Clearance:
In healthy individuals, all filtered glucose is reabsorbed via transporter proteins (SGLT, GLUT); therefore, glucose clearance = 0 mL/min, indicating no glucose is excreted.
This reflects that C{inulin} > C{glucose}, meaning glucose was reabsorbed.
Urea Clearance:
Serves as an example of net reabsorption, where approximately 50% of filtered urea is reabsorbed back into the bloodstream, and filtration exceeds excretion.
This reflects that C{inulin} > C{urea}, meaning urea was reabsorbed.
Penicillin Clearance:
Demonstrates net secretion, where excretion is greater than filtration. Penicillin is actively secreted into the proximal tubule via organic anion transporters.
For example, penicillin clearance can be 150 mL/min, exceeding GFR (e.g., 100 mL/min).
This reflects that C{penicillin} > C{inulin}, indicating active secretion.
Historically, kidneys were very efficient at eliminating penicillin, requiring re-purification from patient urine during early therapeutic use. Pharmaceutical companies closely monitor drug clearance.
Detailed Concept of Renal Clearance
Definition: Renal clearance quantifies the volume of plasma from which a substance has been completely removed in a given time frame (usually measured in mL/min or mL/hour).
Key Concepts in Renal Function
Quantitative Examples (Experimental Calculation):
Experimental Setup:
A lab animal is administered a substance (e.g., drug) via tail vein injection.
The animal is placed in a metabolism cage for a controlled collection time (e.g., 10 hours) to collect urine.
Urine volume and drug concentration in urine are measured.
A blood plasma sample is collected (e.g., halfway through the experiment) to measure drug concentration in plasma.
Calculations:
Excretion Rate (mass/time):
For example, given a urine volume of 10 mL and urine drug concentration of 1 mg/mL over 10 hours:
Excretion (mg/hour) = (\text{urine volume} \times \text{urine concentration}) / \text{collection time}
Excretion (mg/hour) = (10 \text{ mL} \times 1 \text{ mg/mL}) / 10 \text{ hours} = 1 \text{ mg/hour}
Clearance (volume/time):
Clearance = Excretion Rate / Plasma concentration
For example, if plasma concentration is 1 mg/mL:
Clearance = (1 \text{ mg/hour}) / (1 \text{ mg/mL}) = 1 \text{ mL/hour}
Clearance Relationship Equations
For a substance X:
If C{substance\ x} > C{inulin}, substance X is filtered and secreted on a net basis.
If C{substance\ x} < C{inulin}, substance X is filtered and reabsorbed on a net basis.
If C{substance\ x} = C{inulin}, substance X is filtered, not secreted, and not reabsorbed.
Creatinine: A substance used clinically that closely approximates inulin clearance for estimating GFR. It is a breakdown product of phosphocreatine, endogenously produced at a constant rate. While it is both reabsorbed and secreted, these processes largely balance each other, making it a convenient clinical marker.
Sodium and Water Regulation
Key Concepts
Enormous Filtration Volume: GFR is approximately 180 L/day, which is 60 times the plasma volume, highlighting the massive reabsorption required (99% of filtered water).
Reabsorption Mechanisms:
Sodium (Na+): Active transport process driven by the Na^+/K^+ ATPase pump (2 K+ in, 3 Na+ out) in the basolateral membrane. This active transport sets up the osmotic gradient.
Water (H_2O): Reabsorbed osmotically, primarily following Na+ concentration gradients. Water movement is facilitated through aquaporin protein channels. There is no known primary active transport mechanism for water.
Sodium as Major Determinant: Sodium is the major determinant of extracellular fluid volume (ECF).
Independent Regulation: Sodium reabsorption is primarily regulated by aldosterone, while water reabsorption is regulated by vasopressin (ADH).
Regulatory Hormones:
Vasopressin/ADH: Enhances water reabsorption primarily in the collecting ducts by regulating the insertion of aquaporin 2 channels into the apical membrane. Secreted in response to increased blood osmolarity and decreased blood volume/pressure.
Renin-Angiotensin-Aldosterone System (RAAS): Regulates sodium and water balance, ultimately increasing blood pressure. Triggered by decreased blood pressure, leading to renin release, angiotensin II production, and subsequent aldosterone and vasopressin effects.
Atrial Natriuretic Peptides (ANPs): Promote excretion of salt and water (natriuresis and diuresis) to lower blood pressure, primarily by increasing GFR (vasodilation of afferent arteriole) and inhibiting renin release. Released in response to increased blood volume stretching the atrial walls.
Homeostatic Control of Blood Pressure
Volume Receptors: Located in the atria, and baroreceptors (carotid artery and aortic) detect changes in blood volume and pressure.
Responses to Decreased Blood Volume/Pressure: Trigger sympathetic stimulation, vasoconstriction, increased cardiac output, thirst, and kidney water conservation (via RAAS and vasopressin).
Responses to Increased Blood Volume/Pressure: Trigger ANP release, leading to increased GFR and reduced vasopressin, resulting in excretion of excess fluid.
Implications of Kidney Regulation
Fluid Volume Regulation: Must balance between intake and loss. Significant drops in fluid volume can impair renal function (e.g., decrease GFR).
GFR Adjustment:
Decreased fluid volume can cause vasoconstriction of the afferent arteriole, decreasing blood flow and hydrostatic pressure, thus decreasing GFR.
Increased fluid volume (e.g., high water intake) can cause vasodilation of the afferent arteriole, increasing GFR and promoting fluid excretion.
Osmolarity Adjustments in the Nephron
Mechansims of Urine Concentration: The kidney achieves urine concentration by creating an osmotic gradient in the medulla and selectively regulating water permeability.
Cortex vs. Medulla: Fluid entering the proximal tubule is ~300 mOsm. The osmolarity of the medulla progressively increases, reaching up to 1200 mOsm at the inner medulla, primarily due to urea.
Descending Limb of Loop of Henle: Highly permeable to water (aquaporins present), but impermeable to solutes. As tubular fluid descends into the hyperosmotic medulla, water is reabsorbed, increasing the osmolarity of the tubular fluid (e.g., from 300 to 1200 mOsm).
Ascending Limb of Loop of Henle: Impermeable to water (aquaporins absent), but actively reabsorbs ions (e.g., Na+, Cl-). This decreases the osmolarity of the tubular fluid (e.g., from 1200 mOsm to ~100 mOsm).
Distal Tubule and Collecting Duct: These segments exhibit variable reabsorption of water, regulated by hormones based on the body's hydration state, allowing fine-tuning of final urine osmolarity and volume.
Hormonal Regulation of Water Movement
Permeability Control by Aquaporins:
Water movement across collecting duct cell membranes is facilitated by aquaporin channels.
Aquaporin 2 (AQP2): Specifically regulated by vasopressin (ADH).
Mechanism of Vasopressin Action:
Vasopressin (peptide hormone) is produced in the hypothalamus and released from the posterior pituitary in response to increased blood osmolarity or decreased blood volume/pressure (detected by osmoreceptors and baroreceptors/atrial stress receptors).
Vasopressin binds to a G-protein coupled receptor on the basolateral membrane of collecting duct cells.
This activates a signaling cascade (via cyclic AMP and protein kinase A).
Protein kinase A phosphorylates AQP2 channels, leading to the exocytosis of vesicles containing AQP2 to the apical membrane (the membrane facing the tubular lumen).
The insertion of AQP2 channels into the apical membrane increases its permeability to water, allowing water to diffuse down its osmotic gradient and be reabsorbed.
Other aquaporin isoforms are always present on the basolateral membrane, ensuring continuous water movement out of the cell once it enters.
Pathophysiology of Diabetes Insipidus
Definition: Characterized by polyuria (excessive urination) and inability to concentrate urine, leading to large volumes of dilute, tasteless (insipid) urine without glucose.
Types of Diabetes Insipidus:
Central Diabetes Insipidus: Caused by a loss of vasopressin production in the hypothalamus/posterior pituitary (central nervous system origin).
Nephrogenic Diabetes Insipidus: Caused by a loss of vasopressin receptors or an inability of collecting duct cells to respond to vasopressin.
Mechanism: In both types, AQP2 vesicles fail to traffic to the apical membrane, preventing water reabsorption in the collecting duct. This results in water diuresis.
Main Points on Diabetes Mellitus Effects
Definition: Characterized by hyperglycemia (excess sugar in the blood) due to inadequate insulin production or impaired insulin sensitivity. The word "mellitus" means sweet.
Hyperglycemia and Its Consequences (Osmotic Diuresis):
Glucosuria: High blood glucose levels exceed the renal transport maximum for glucose reabsorption, resulting in glucose in the urine.
Polyuria: Glucose in the tubular fluid acts as an osmotically active solute, preventing water reabsorption and leading to excessive urination (osmotic diuresis).
Polydipsia: Increased thirst due to fluid loss.
Polyphagia: Increased hunger (especially in uncontrolled type 1 diabetes).
Renin-Angiotensin-Aldosterone System (RAAS): Mechanisms
Overview: A crucial hormonal system for regulating blood pressure and fluid balance.
Components and Pathway:
Angiotensinogen: A precursor protein produced constitutively by the liver and circulating in the bloodstream, ready to be activated.
Renin Release: Renin is an enzyme (not a hormone) produced and secreted by granular cells (modified smooth muscle cells) in the afferent arteriole. Renin release is triggered by:
Decreased blood pressure (direct effect on granular cells).
Decreased GFR/flow rate past the macula densa cells (macula densa releases paracrine factors like prostaglandins).
Increased sympathetic stimulation of granular cells (from cardiovascular control centers in the medulla).
Angiotensin I Formation: Renin cleaves angiotensinogen to form angiotensin I (Ang I), an inactive precursor.
Angiotensin II Formation: Angiotensin Converting Enzyme (ACE) converts Ang I to angiotensin II (Ang II), the biologically active hormone.
ACE inhibitors (e.g., lisinopril) block this conversion, used clinically to lower blood pressure.
Actions of Angiotensin II (Ang II): Ang II increases blood pressure and blood volume through multiple mechanisms:
Stimulates vasopressin (ADH) release from the posterior pituitary, leading to increased water reabsorption in the collecting ducts.
Stimulates aldosterone synthesis and release from the adrenal cortex, promoting Na+ reabsorption and K+ secretion in the collecting ducts.
Causes widespread vasoconstriction of arterioles (especially in the GI tract and skin), increasing total peripheral resistance and blood pressure.
Increases sympathetic stimulation of the heart and blood vessels via effects on the medulla, increasing cardiac output and vasoconstriction.
Promotes sodium reabsorption in the proximal tubule.
Role of Aldosterone in Renal Physiology
Source: A steroid hormone produced by the adrenal cortex. It is not stored but synthesized on demand.
Triggers for Release:
Primary: Angiotensin II (from the RAAS pathway) in response to decreased blood pressure/volume.
Secondary: Elevated plasma potassium (hyperkalemia), which directly stimulates the adrenal cortex to release aldosterone.
Mechanism of Action:
Aldosterone, being a steroid hormone, diffuses into collecting duct cells (P cells) and binds to an intracellular receptor.
This complex regulates gene expression (at the level of transcription), leading to the synthesis of new transport proteins (channels and pumps).
Effects: Enhances Na+ reabsorption (primarily by increasing Na^+ channels on the apical membrane and Na^+/K^+ ATPase activity on the basolateral membrane) and K+ secretion (by increasing K^+ channels on the apical membrane).
Overall Impact: Increased sodium reabsorption creates an osmotic gradient that drives water reabsorption (if aquaporins are present), thereby increasing blood volume and pressure, and helps excrete excess potassium. The electrogenic nature of the Na^+/K^+ ATPase (3 Na^+ out, 2 K^+ in) ensures a net movement of ions that drives water reabsorption more effectively.
Potassium Homeostasis: Critical for excitable cell function (e.g., heart). Hyperkalemia (elevated blood K+) causes depolarization and can lead to cardiac arrhythmias. Hypokalemia (low blood K+) causes hyperpolarization, leading to muscle weakness (e.g., diaphragm) and cardiac arrhythmias.
Atrial Natriuretic Peptides (ANPs)
Function: Hormones primarily involved in lowering blood pressure and volume.
Source: Released by specialized endocrine cells in the atria of the heart (primarily the left atrium).
Trigger for Release: Increased blood volume and pressure, which causes stretching of the atrial walls.
Mechanism of Action:
Causes vasodilation of the afferent arteriole in the kidney, which reduces resistance, increases blood flow to the glomerulus, and increases hydrostatic pressure, leading to an increase in GFR.
Inhibits the release of renin, thereby reducing the production of angiotensin II and its vasoconstrictive and aldosterone-stimulating effects.
Promotes natriuresis (excretion of Na+) and diuresis (excretion of water), decreasing total body sodium and fluid volume.
Overall Effect: Decreases blood volume and blood pressure, counteracting the effects of the RAAS.
Summary of Renal Regulations
Key Hormonal Influences: The renal system involves a complex synergy of hormones (Vasopressin, Aldosterone, Angiotensin II, ANPs) and physiological responses to tightly regulate fluid, electrolyte (especially Na+ and K+), and osmotic balance. This intricate regulation is essential for maintaining whole-body homeostasis and ensuring appropriate blood pressure and volume.