Week 4 Therapy of renal tubulopathies (jojanneke huck phd,
neurophysiologist department of medical biosciences RUMC)
SMDs/peptides targeting ion levels in renal tubulopathies
Renal Physiology
Ion channels in renal physiology, are also found in the brain with similar function.
Kidney functions: homeostasis of electrolytes, metabolites and acid-base, regulation of water
excretion (osmolarity and volume of extracellular fluids, excretion of waste/toxic products,
production and secretion of hormones, excretion of non-physiological substances (e.g. drugs).
A human has about 7 liters of blood, during 1 day 1400 liter pass the kidneys. 60-70 percent is
filtered through glomerulus (hangs in bowman’s capsule). 180 liters of ultrafiltrate (pre-urine). 1,5
liters of urine per day. So 178 liters is reabsorbed again.
Large proteins and blood cells cant pass the filter. Albumin in urine means filter doesn’t work well.
Kidney diseases (10% of Dutch population has kidney disease). About 6500 people on dialysis (every
3 days 4 hours long). About 1000 kidneys donation every year and 900 on waiting list (waiting time 4
years). Annually for 250 persons too late.
Urine is 95% water, 2,5% ureum (waste product from metabolism), 2,5% complex mixture of
minerals, hormones, vitamins, and enzymes.
If kidney malfunctions you can see it in other organs because they are all connected.
Kidneys regulate osmolarity by excreting water (less fluid, osmolarity rises) under control of
vasopressin. Control body fluid volume (blood volume) by sodium excretion (renin-angiotensin-
aldosterone system (RAAS)).
The ions channels and other transporters are the gatekeepers which can be regulated. Expression
regulates absorption and excretion.
1 million nephrons in kidneys (from 50% lost is a problem). Cortex outside and medulla inside kidney
- Glomerulus
o Podocytes on the outside of the vascular layer: have long end fingers that wrap
around the vascular system (the glomerulus). Size selective
o GBM = Glomerulus base membrane: charge and fold selective
o Afferent (gets blood in) and efferent arteriole (gets blood out)
, o BS = bowman’s space
o
o Clearance = measurement how quickly a substance leaves the blood plasma.
Filtration – absorption + secretion = excretion/clearance.
o Creatinine = waste products from muscles, which is not absorbed or secreted after
glomerulus. So creatinine amount in urine and plasma can be used to calculate
kidney function.
- PCT = Proximal convoluted tubule: reabsorption of minerals and water.
o Paracellular transport: it goes in between the cells to the blood. More leaky
epithelium in PT than in DCT
o Transcellular transport: cross 2 membranes to get to the blood
- Intermediate tubule the lis of Henle: descending and ascending part
o TLD = Descending: no sodium transport. Water resorption
o TLA = Ascending: not permeable for water but for sodium transport
- DCT = distal convoluted tubule
o First part of DCT is TAL = thick ascending loop of Henle: leaky epithelium (still sodium
reabsorption, mg transport)
o Second part of DCT is DCT = tight epithelium. Transcellular transport with more tight
junctions. Still some sodium reabsorption
- CNT = connecting tubules
- CD = collecting duct: still some sodium transporters present, potassium excretion and proton
secretion (influence acid-base balance).
Hormones or blockers can influence specific transporters inside cells of the nephrons. Translation,
storage, degradation, etc can be regulated by hormones, mutations, medicine, etc.
Current studies and therapy of renal tubulopathies
High need for calcium (bone density and signaling) and magnesium. Often with kidney problems
there is a calcium imbalance. Problem in TAL, too little magnesium in blood causes many symptoms.
For exam don’t know names by heart, an explanation of where the mutation is will be given. You
have to have an insight of how it is regulated.
How to test the 3 functional defects in channels/transporters:
- Decreased activity at the membrane, inactivated channel, impaired gating (ion selectivity)
o Test with tracer ions, how well is it taken up
o Patch clamp: suck up part of membrane (containing an ion channel) with hollow
pipet, and measure the currency. Voltage change when ions go through.
neurophysiologist department of medical biosciences RUMC)
SMDs/peptides targeting ion levels in renal tubulopathies
Renal Physiology
Ion channels in renal physiology, are also found in the brain with similar function.
Kidney functions: homeostasis of electrolytes, metabolites and acid-base, regulation of water
excretion (osmolarity and volume of extracellular fluids, excretion of waste/toxic products,
production and secretion of hormones, excretion of non-physiological substances (e.g. drugs).
A human has about 7 liters of blood, during 1 day 1400 liter pass the kidneys. 60-70 percent is
filtered through glomerulus (hangs in bowman’s capsule). 180 liters of ultrafiltrate (pre-urine). 1,5
liters of urine per day. So 178 liters is reabsorbed again.
Large proteins and blood cells cant pass the filter. Albumin in urine means filter doesn’t work well.
Kidney diseases (10% of Dutch population has kidney disease). About 6500 people on dialysis (every
3 days 4 hours long). About 1000 kidneys donation every year and 900 on waiting list (waiting time 4
years). Annually for 250 persons too late.
Urine is 95% water, 2,5% ureum (waste product from metabolism), 2,5% complex mixture of
minerals, hormones, vitamins, and enzymes.
If kidney malfunctions you can see it in other organs because they are all connected.
Kidneys regulate osmolarity by excreting water (less fluid, osmolarity rises) under control of
vasopressin. Control body fluid volume (blood volume) by sodium excretion (renin-angiotensin-
aldosterone system (RAAS)).
The ions channels and other transporters are the gatekeepers which can be regulated. Expression
regulates absorption and excretion.
1 million nephrons in kidneys (from 50% lost is a problem). Cortex outside and medulla inside kidney
- Glomerulus
o Podocytes on the outside of the vascular layer: have long end fingers that wrap
around the vascular system (the glomerulus). Size selective
o GBM = Glomerulus base membrane: charge and fold selective
o Afferent (gets blood in) and efferent arteriole (gets blood out)
, o BS = bowman’s space
o
o Clearance = measurement how quickly a substance leaves the blood plasma.
Filtration – absorption + secretion = excretion/clearance.
o Creatinine = waste products from muscles, which is not absorbed or secreted after
glomerulus. So creatinine amount in urine and plasma can be used to calculate
kidney function.
- PCT = Proximal convoluted tubule: reabsorption of minerals and water.
o Paracellular transport: it goes in between the cells to the blood. More leaky
epithelium in PT than in DCT
o Transcellular transport: cross 2 membranes to get to the blood
- Intermediate tubule the lis of Henle: descending and ascending part
o TLD = Descending: no sodium transport. Water resorption
o TLA = Ascending: not permeable for water but for sodium transport
- DCT = distal convoluted tubule
o First part of DCT is TAL = thick ascending loop of Henle: leaky epithelium (still sodium
reabsorption, mg transport)
o Second part of DCT is DCT = tight epithelium. Transcellular transport with more tight
junctions. Still some sodium reabsorption
- CNT = connecting tubules
- CD = collecting duct: still some sodium transporters present, potassium excretion and proton
secretion (influence acid-base balance).
Hormones or blockers can influence specific transporters inside cells of the nephrons. Translation,
storage, degradation, etc can be regulated by hormones, mutations, medicine, etc.
Current studies and therapy of renal tubulopathies
High need for calcium (bone density and signaling) and magnesium. Often with kidney problems
there is a calcium imbalance. Problem in TAL, too little magnesium in blood causes many symptoms.
For exam don’t know names by heart, an explanation of where the mutation is will be given. You
have to have an insight of how it is regulated.
How to test the 3 functional defects in channels/transporters:
- Decreased activity at the membrane, inactivated channel, impaired gating (ion selectivity)
o Test with tracer ions, how well is it taken up
o Patch clamp: suck up part of membrane (containing an ion channel) with hollow
pipet, and measure the currency. Voltage change when ions go through.
