Mechanisms for protein catabolism in uremia: metabolic acidosis and activation of proteolytic pathways.
Accelerated protein catabolism in uremia occurs in animals and patients with acute (ARF) and chronic renal failure (CRF). Possible causes include resistance to both insulin-induced inhibition of protein-degradation and insulin-induced stimulation of protein synthesis. The mechanisms for these effects are unknown. However, metabolic acidosis has been shown to increase proteolysis in rat skeletal muscle even in the presence of insulin and this effect is absent in adrenalectomized rats. Similarly, metabolic acidosis accounts for increased muscle proteolysis in rats with CRF. Metabolic acidosis also stimulates branched-chain amino acid (BCAA) breakdown by increasing the activity of branched-chain keto acid decarboxylase. Uremia causes high corticosterone levels in ARF and CRF and this hormone could contribute significantly to increased proteolysis, BCAA-breakdown and possibly, the inhibition of protein synthesis. Besides changing glucocorticoids, uremia could inhibit the activity of transporters which regulate intracellular pH and ultimately, the metabolism of protein and amino acids. For example, uremia inhibits ion transporters including Na/H exchange in a variety of tissues and therefore, could increase the susceptibility to metabolic acidosis. Research directed at identifying specific, proteolytic pathways stimulated by metabolic acidosis has excluded a major role for Ca2+ activated and lysosomal proteases and suggests activation of an ATP- and ubiquitin-dependent proteolytic pathway.
Greiber
S
S
Renal Division, Emory University School of Medicine, Atlanta, GA.
Mitch
W E
WE
D000138:Acidosis / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D014511:Uremia / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*
D000597:Amino Acids, Branched-Chain; D005938:Glucocorticoids; D009124:Muscle Proteins; D010447:Peptide Hydrolases