The role of free fatty acids in hypoxia-induced injury to renal proximal tubule cells.
Phospholipase activation with resulting phospholipid breakdown and lipid byproduct accumulation may play a critical role in hypoxic cell injury. To explore this role, mildly hypoxic rabbit renal proximal tubules (PT) in suspension were treated in vitro with exogenous phospholipase A2 (PLA2). This treatment produced severe tubule cell injury measured by alterations in tubule cation homeostasis, respiratory rates, and adenosine nucleotide metabolism. This injury was associated with loss of the major membrane phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), with accumulation of lipid byproducts, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and free fatty acids (FFA). Addition of fatty acid-free bovine serum albumin (BSA) to PTs reduced markedly FFA levels and improved significantly derangements in metabolic parameters of hypoxic PTs treated with exogenous PLA2, suggesting that FFA accumulation was a critical factor in this injury process. Effects of increasing durations of hypoxia (30, 45, and 60 min) with or without reoxygenation recovery demonstrated increased FFA levels, especially polyunsaturated FFA, which correlated better with the degree of hypoxic injury than alterations in membrane phospholipid and lysophospholipid levels. PTs undergoing hypoxia and reoxygenation recovery exposed to BSA were not protected. Although 60 min of hypoxia with 60 min reoxygenation produced accumulation of FFA to levels nearly identical to those seen in hypoxic PTs treated with exogenous PLA2 and BSA, with a similar distribution of various FFA species, hypoxia/reoxygenation produced a more severe degree of cell injury than that observed with hypoxia plus exogenous PLA and BSA.(ABSTRACT TRUNCATED AT 250 WORDS)
Humes
H D
HD
Department of Internal Medicine, Veterans Administration Medical Center, Ann Arbor, Michigan.
Nguyen
V D
VD
Cieslinski
D A
DA
Messana
J M
JM
D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000502:physiology; D010741:Phospholipases A / Q000494:pharmacology; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D011817:Rabbits
D005230:Fatty Acids, Nonesterified; D010743:Phospholipids; D010741:Phospholipases A; D054467:Phospholipases A2; D010100:Oxygen