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Clean blood of wast products, mainly small water-soluble molecules.
Kidney functional unit that connects blood supply to urinary excretion pathway. ~ 1 million in body.
Network of porous capillaries where fluid seeps out of circulation.
Funnels fluid into the tubule but prevents >60 kDa proteins from entering. Small metabolites/proteins pass through unless bound to large proteins (albumin).
Reabsorbs important metabolites, nutrients, and water (reducing volume by 80%). Outside of proximal tubule is fluid from renal corpuscle where toxic compounds are absorbed into the lumen. High energy dependance so lots of mitochondria and cytochrome P450.
Less targeted tubule. Ethanol and caffeine target to lessen water re-absorption so increase urination.
Use of high concentration to make sure all bacteria are dead (even semi-resistant ones).
Toxic potential from amine groups. More makes it more toxic.
Aminoglycoside antibiotic toxic pathway
Positive amine groups bind to phospholipids, taken in by endocytosis and sent to lysosome. Lysosome can't degrade well and builds up to the point where leakage of degradative enzyme causes cell death.
Mitochondria sensitive to antibiotic because of prokaryotic ancestor. Damage leads to loss of energy function and necrosis in proximal tubule.
Heavy Metal Toxicity
Hg, Zn, Au, Pb, Cd, cisplatinum (anticancer), Ba (X-ray).
Attacks sulfhydryl group of proteins which leads to protein damage. Targets surface membrane constituents (ion channel) or mitochondria. Glutathione protects cell.
Metallothionein pares liver but damages kidney.
High level of Zn and Cd stimulates this small protein (~10 kDa) which binds to metals and reduce exposure.
However because it is a small protein it passes the glomerulus easily is degraded by the lysosome of proximal tubule cells. This releases the metal which damages the cells.
Gasoline causes kidney cancer in male rats but not in females or mice. Culprit is due to iso-octane and saturated alkanes.
a2-microglobulin (~20 kDa) stimulated by androgens (higher in male) which normally is absorbed by proximal tubule cells and degraded in lysosome to amino acids.
Iso-octane binds to a2-microglobulin and forms hyaline droplets (protein globs) in lysosome and leaks hydrolytic enzymes into the cell --> cell death.
Male rats sensitive. Formation of a2-microglobulin in urine which damages bladder epithelium leading to increased cell cycle (tumor promoter).
Acetaminophen is considered safe unless it is long-term or high dose. Usually conjugated at phenolic hydroxyl but a minor pathway is amine hydroxylation to form an iminoquinone (DNA and protein adduct).
Acetaminophen sensitivity in rats vs. mouse
Mouse are more sensitive b/c they have more cytochrome P450 which is responsible for amine hydroxylation.
Rats have more glutathione which neutralize iminoquinone.
Iso-octane sensitivity in male vs. female rats
- Female rats don't have as much androgen and thus have less a2-microglobulin so less damage to kidneys.
- Female rats injected with a2-microglobulin that are exposed to gasoline show kidney damage and cancer.
Reacts with halogenated hydrocarbon to form adducts