• Negative feedback reverses a change and brings a factor back to normal — this is how most homeostasis works.
• Positive feedback pushes a factor further away from normal — useful for quick, one-off events like childbirth or blood clotting, but NOT part of homeostasis.
• Homeostasis keeps internal conditions (temperature, blood glucose, water potential) within narrow limits so enzymes and cells work properly.
• Thermoregulation uses skin structures (arterioles, sweat glands, hair erector muscles) and the hypothalamus to control body temperature via nervous and hormonal responses.
• The kidney is both an osmoregulatory organ (controls water content of blood) and an excretory organ (removes urea and excess salts).
• Urea is made in the liver by deamination of excess amino acids, forming ammonia, which is converted to less-toxic urea via the ornithine cycle.
• Ultrafiltration in the glomerulus/Bowman's capsule forces small molecules out of the blood under high pressure.
• Selective reabsorption in the proximal convoluted tubule reclaims useful substances (glucose, amino acids, salts, water) back into the blood.
• The loop of Henle acts as a countercurrent multiplier, creating a very concentrated medulla so water can be reabsorbed and urine concentrated.
• ADH, released by the posterior pituitary, controls how much water is reabsorbed in the distal convoluted tubule and collecting duct by adjusting aquaporin numbers.
• Hormones control gene expression either directly (steroid/thyroid hormones acting as transcription factors) or indirectly (peptide hormones using second messengers like cAMP).

Think of negative feedback like the thermostat in a house. If the room gets too cold, the heating switches on. Once it's warm enough, the heating switches off again. The system is always trying to pull things back toward a set point — it never lets the temperature drift too far in one direction.

In the body, the same logic applies to things like body temperature, blood glucose, and water balance. Every negative feedback loop has the same basic cast of characters:

• Receptor — detects a stimulus (a change in a physiological factor, e.g. a drop in temperature).
• Coordination system — passes the message along, either via the nervous system (fast, short-lived) or the hormonal system (slower, longer-lasting).
• Effector — a muscle or gland that actually carries out the response.

The key outcome: if a factor rises above normal, the response makes it decrease. If a factor falls below normal, the response makes it increase. This is why almost every negative feedback system actually has two separate corrective mechanisms built in — one for "too high" and one for "too low" — so the factor keeps oscillating gently around the set point rather than sitting exactly on it (this is called dynamic equilibrium).

Positive feedback does the opposite of negative feedback: instead of cancelling out the original change, it amplifies it. This sounds dangerous (and often is if it runs unchecked), but it's genuinely useful when the body needs to trigger something quickly and decisively.

Homeostasis is the maintenance of a constant internal environment — but "constant" doesn't mean "unchanging," it means "fluctuating gently around a normal set point" (dynamic equilibrium). Why does the body bother? Because cells — and especially enzymes — are extremely fussy about their working conditions.

Why Temperature Matters

Enzymes rely on precise hydrogen bonding to hold their 3D shape (including the active site) in place. If body temperature rises too far above the optimum (e.g. above 40°C), the extra kinetic energy breaks these hydrogen bonds. The active site changes shape, becomes non-complementary to the substrate, and the enzyme can no longer form an enzyme-substrate complex — meaning metabolic reactions slow down or stop. This is denaturation, and unlike a temporary inhibition, it's usually permanent.

Why Blood Glucose Matters

Cells need a constant supply of ATP, and glucose is the main respiratory substrate used to generate it. Too little glucose starves cells of energy; too much disrupts water potential balance (osmotic problems). Cells in the pancreas monitor and respond to blood glucose levels.

Why Water Matters

Water makes up the cytoplasm and is a reactant/product in many metabolic reactions (including respiration and the ornithine cycle you'll meet later). It's lost continuously through urine and sweat, so the kidneys must carefully regulate how much stays in the blood.

Thermoregulation relies on the skin (as an effector organ) and the hypothalamus (as the coordination centre). It's easiest to learn this as two opposite toolkits: a cooling toolkit and a warming toolkit — both control the same three structures (blood vessels, sweat glands, hair muscles), just running in opposite directions.

Cooling Mechanisms (body too hot)

Warming Mechanisms (body too cold)

The kidney does two jobs simultaneously: it's an osmoregulatory organ (controls the water content of the blood — critical for blood pressure and preventing osmotic cell damage) and an excretory organ (removes toxic waste like urea and excess salts).

Gross Structure

Beneath the outer fibrous capsule, the kidney has three regions: the cortex (outer), medulla (inner), and renal pelvis (central, connects to the ureter).

The Nephron — the Functional Unit

Each kidney contains thousands of nephrons — tiny tubules responsible for forming urine. Different parts of one nephron sit in different regions of the kidney:

• Cortex: glomerulus, Bowman's capsule, proximal convoluted tubule, distal convoluted tubule.
• Medulla: loop of Henle, collecting duct.
• Renal pelvis: where all nephrons drain before urine travels down the ureter.

There are two nephron types: cortical nephrons (~85% of nephrons, short loop of Henle barely entering the medulla) and juxtamedullary nephrons (long loop of Henle spanning the whole medulla — very efficient at conserving water).

Blood Supply to Each Nephron

The afferent arteriole (from the renal artery) supplies the glomerulus — a knot of capillaries inside Bowman's capsule. These capillaries rejoin to form the narrower efferent arteriole, and blood then flows into a capillary network running alongside the rest of the nephron before eventually draining into the renal vein.

The body can't store excess amino acids the way it stores excess glucose (as glycogen) or excess fat. So excess amino acids have to be broken down and disposed of — this all happens in the liver.

Deamination

Liver cells (hepatocytes) remove the amino group (–NH₂) from excess amino acids, along with an extra hydrogen atom. These combine to form ammonia (NH₃).

The leftover keto acid isn't wasted — it can be respired directly (entering the Krebs cycle), converted to glucose, or converted to glycogen/fat for storage. So the "carbon skeleton" of the amino acid still gets used as a useful energy source; it's only the nitrogen-containing amino group that becomes waste.

The Ornithine Cycle

Ammonia is extremely toxic, so the liver converts it quickly into much-less-toxic urea through a series of steps called the ornithine cycle:

Urea then travels in the blood plasma to the kidneys, where it's filtered out of the blood into Bowman's capsule by ultrafiltration, and ultimately excreted in urine.

Ultrafiltration happens at the glomerulus and Bowman's capsule. Blood in the glomerular capillaries is at high pressure (because the afferent arteriole is wider than the efferent arteriole). This high pressure forces small molecules out of the capillaries and into Bowman's capsule, forming the glomerular filtrate.

There are two cell layers plus a basement membrane between the blood and Bowman's capsule lumen:

• Capillary endothelium — has gaps that let fluid through.
• Basement membrane — mesh-like, acts as the actual filter, stopping large protein molecules.
• Bowman's capsule epithelium — has gaps that let small molecules through.

Not everything in the filtrate is waste — glucose, amino acids, salts, and most of the water are actually useful and shouldn't be lost in urine. So as the filtrate flows along the nephron, useful substances get reabsorbed back into the blood. Most of this happens in the PCT.

Why the PCT is Built for This Job

The Mechanism, Step by Step

1. Sodium-potassium pumps (using ATP from mitochondria) actively pump Na⁺ OUT of the PCT epithelial cells, across the basal membrane, into the blood.
2. This lowers the Na⁺ concentration inside the cell, so Na⁺ moves passively down its concentration gradient from the tubule lumen INTO the cell, via co-transporter proteins.
3. These co-transporter proteins simultaneously drag glucose and amino acids into the cell alongside the Na⁺ (this is called facilitated diffusion coupled to active transport — technically the glucose/amino acid movement itself is passive, powered indirectly by the Na⁺ gradient that active transport created).
4. Glucose and amino acids then diffuse out of the cell into the blood via transport proteins in the basal membrane.
5. The movement of solutes out of the tubule lowers the water potential of the surrounding tissue, so water follows by osmosis.
6. Urea moves out by simple diffusion, down its concentration gradient.

This is the trickiest diagram in the chapter, so let's slow right down. The loop of Henle's whole job is to create urine that's more concentrated than the blood — i.e. to conserve water that would otherwise be lost.

The trick is a countercurrent multiplier system: "countercurrent" means the filtrate flows in opposite directions in the two limbs (descending goes down into the medulla, ascending goes back up out of it), and "multiplier" means this opposite flow lets the loop build up an increasingly steep, very concentrated solute gradient in the medulla tissue — much steeper than a simple one-way system could ever achieve.

Ascending Limb

• Impermeable to water — no water can leave here by osmosis, no matter what.
• Na⁺ and Cl⁻ ions are actively pumped OUT into the surrounding medulla (diffusion in the lower part, active transport in the upper part).
• This lowers the water potential of the medulla tissue around it.
• Because ions leave but water can't, the filtrate inside the ascending limb gets progressively LESS concentrated (higher water potential) as it rises back toward the cortex.

Descending Limb

• Permeable to water, but has few ion transport proteins (low permeability to ions).
• Because the ascending limb has made the surrounding medulla tissue very concentrated (low water potential), water moves OUT of the descending limb by osmosis, into the tissue.
• The filtrate inside the descending limb becomes progressively MORE concentrated as it travels deeper into the medulla.

The end result: as you go deeper into the medulla, the tissue fluid gets progressively more concentrated (this is why juxtamedullary nephrons with long loops reaching deep into the medulla are so good at conserving water — they create a much steeper, deeper gradient). The water and ions that leave the loop are picked up by the surrounding capillary network and returned to general circulation, not lost.

The distal convoluted tubule and collecting duct are where the body makes its "final adjustment" to how concentrated urine is — and this fine-tuning is controlled by a hormone called antidiuretic hormone (ADH).

The Full Pathway

1. Osmoreceptors in the hypothalamus continuously monitor the water potential of the blood.
2. If blood water potential decreases (blood too concentrated / dehydration risk), nerve impulses travel along sensory neurons to the posterior pituitary gland.
3. This stimulates the posterior pituitary to release more ADH into the blood.
4. ADH travels to its target cells — the distal convoluted tubule (DCT) and collecting duct.
5. ADH increases the permeability of these tubule walls to water, so MORE water is reabsorbed into the blood.
6. Result: a small volume of concentrated urine, and blood water content rises back to normal.

How ADH Actually Changes Permeability — The Aquaporin Mechanism

This is a great example of cell signalling at the molecular level, and it's a common source of exam questions:

1. ADH binds to receptor proteins on the cell surface membrane of collecting duct cells.
2. This triggers a signalling cascade inside the cell.
3. Vesicles inside the cell — whose membranes are packed with water-channel proteins called aquaporins — move toward and fuse with the luminal membrane (the membrane facing the tubule lumen).
4. This inserts many more aquaporins into the luminal membrane, dramatically increasing its permeability to water.
5. Water then moves through the aquaporins, down the water potential gradient, out of the tubule and into the concentrated tissue fluid/blood of the medulla.

Hormones don't just trigger instant physical responses — many of them work by switching genes on or off. This happens via transcription factors: proteins that bind to specific regions of DNA and control whether a gene gets transcribed. Roughly 10% of human genes code for transcription factors, and they come in two flavours: activators (increase expression) and repressors (decrease expression).

There are two very different routes hormones use to influence gene expression, depending on whether they can cross the cell surface membrane.

Route 1 — Hormones That Cross the Membrane (Steroid & Thyroid Hormones)

Steroid hormones and thyroid hormones (like thyroxine) are lipid-soluble, so they can slip straight through the phospholipid bilayer and enter the nucleus, where they bind directly to transcription factors.

Route 2 — Hormones That Cannot Cross the Membrane (Peptide/Protein Hormones)

Hormones like adrenaline, insulin, glucagon, and ADH are proteins or peptides — too large and not lipid-soluble, so they can't cross the membrane. Instead, they bind to a specific receptor sitting IN the cell surface membrane, which triggers an internal chain reaction:

1. Hormone (the "first messenger") binds to its membrane receptor.
2. This activates an enzyme (e.g. adenylyl cyclase) inside the membrane.
3. This enzyme converts ATP into a "second messenger" molecule — commonly cyclic AMP (cAMP).
4. cAMP activates enzymes called protein kinases.
5. Active protein kinases trigger a cascade of further reactions inside the cell.
6. This cascade can ultimately change the activity of transcription factors, altering gene expression.

Key Equations

• I can describe the components of a negative feedback loop (receptor, coordination system, effector) and explain how it corrects a change.
• I can explain why positive feedback is not part of homeostasis, using childbirth or blood clotting as an example.
• I can explain why homeostasis is important for enzyme function, blood glucose, and water balance.
• I can describe cooling mechanisms (vasodilation, sweating, hairs flattening) and warming mechanisms (vasoconstriction, shivering, thyroxine, hairs erecting).
• I know vasodilation/vasoconstriction happen in arterioles, NOT capillaries.
• I can describe the role of the hypothalamus and thermoreceptors in thermoregulation.
• I can label the gross structure of the kidney and the nephron, including cortex, medulla, and renal pelvis.
• I understand the afferent arteriole is wider than the efferent arteriole, and why this matters.
• I can explain deamination and the ornithine cycle, and why ammonia is converted to urea.
• I can explain how ultrafiltration produces glomerular filtrate, and what is/isn't filtered out.
• I can describe the adaptations of the PCT for reabsorption (microvilli, co-transporters, mitochondria, tight packing).
• I can explain the role of sodium ions in driving glucose/amino acid/water reabsorption in the PCT.
• I can explain the countercurrent multiplier mechanism of the loop of Henle (ascending vs descending limb).
• I can trace the full ADH pathway from osmoreceptors to changes in urine concentration.
• I can explain the aquaporin/vesicle mechanism by which ADH changes membrane permeability.
• I can explain how lipid-soluble hormones (e.g. thyroxine) act directly on transcription factors.
• I can explain the second messenger (cAMP) pathway used by non-lipid-soluble hormones like adrenaline.