Macula densa and tubuloglomerular feedback
Distal tubule · NKCC2 sensor Adenosine A1 Renin
Specialised plaque of cells where the thick ascending limb returns to touch its own glomerulus between the afferent and efferent arterioles. It senses NaCl delivery through NKCC2 and feeds back on afferent tone and renin release, completing the juxtaglomerular apparatus.
Traced from the start
- Glomerular filtration barrier
- Proximal tubule: Na+/H+ exchange and bicarbonate reclamation
- Thick ascending limb of Henle (NKCC2)
- Macula densa and tubuloglomerular feedback
Detail
- Senses
- Luminal NaCl concentration via NKCC2 uptake (normally ~20-60 mmol/L at this site)
- High NaCl delivery
- Macula densa releases ATP, converted to adenosine, which constricts the afferent arteriole through A1 receptors so GFR falls (negative feedback within ~10 s); renin release is suppressed
- Low NaCl delivery
- PGE2 and nitric oxide dilate the afferent arteriole and stimulate renin release from JG cells; angiotensin II then constricts the efferent and restores GFR
- Function
- With the myogenic response, TGF keeps GFR and distal delivery stable across MAP ~80-180 mmHg, protecting the limited distal Na+-reabsorbing capacity from being overwhelmed
- Diuretic interaction
- Loop diuretics block macula densa NKCC2: TGF is switched off (GFR does not fall despite the huge distal delivery) and renin release is stimulated
When it goes wrong
Early diabetes: SGLT2 upregulation raises proximal reabsorption and starves the macula densa of NaCl
Afferent dilatation and glomerular hyperfiltration, the first haemodynamic step toward diabetic nephropathy
SGLT2 inhibitor restoring distal NaCl delivery
TGF re-engages and afferent tone returns: intraglomerular pressure falls, giving an expected acute eGFR dip of ~3-5 mL/min followed by long-term renoprotection
NSAID plus ACE inhibitor or ARB plus diuretic ('triple whammy')
Loss of afferent dilatation, loss of efferent constriction and volume depletion combine to cause pre-renal acute kidney injury
Loop diuretic therapy
Macula densa-driven renin release adds secondary hyperaldosteronism to the K+ and H+ losses
Practise this structure
1 question in the bank tagged Glomerular Filtration.