Laboratory Investigation

Kidney International (1984) 26, 153–161; doi:10.1038/ki.1984.149

Lipid alterations induced by renal ischemia: Pathogenic factor in membrane damage

Erve Matthys1, Yogendra Patel1, Jeffrey Kreisberg1, James H Stewart1 and Manjeri Venkatachalam1

1Department of Pathology, The University of Texas Health Science Center, San Antonio, Texas

Correspondence: Dr M A Venkatachalam, Department of Pathology, The University of Texas, Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA

Received 25 April 1983; Revised 20 January 1984.

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Abstract

Lipid alterations induced by renal ischemia: Pathogenic factor in membrane damage. Lipids of the renal cortex and outer stripe of outer medulla were analyzed in rats during ischemia and 2 hr after blood re-flow. After 15 min of ischemia, there were marked elevations of free fatty acids (FFA) and diacylglycerol (DG), increasing further at 60 min. Percentile increases were greater for polyunsaturated FFA. These elevations were accompanied by alterations in phospholipids (PL): Elevations of lysophosphatidylcholine (LPC) at 15 min, phosphatidic acid at 15 and 60 min, and declines of phosphatidylcholine and phosphatidylinositol at 60 min. Triacylglycerol (TG) showed only modest decline, at 60 min, and in insufficient degree to account for increments in FFA and DG. Two hours after 15 min of ischemia, LPC returned to control levels and other PL were normal except phosphatidylinositol which was decreased, and phosphatidic acid, which remained elevated. FFA and DG approached or reached control values. Two hours after 60 min of ischemia, LPC, FFA, DGs and phosphatidic acid remained elevated; phosphatidylcholine and phosphatidylinositol remained decreased. Histological injury was seen 2 and 24 hr after blood reflow only in kidneys injured by 60 min of ischemia. Thus, irreversible ischemic damage correlates with persistent abnormalities of phosphatidylcholine metabolism and persistent elevations of FFA, LPC, and DG. It is not known whether lipids break down at normal or accelerated rates during ischemia. In this context, accumulation of lipid breakdown products in ischemic cells may be due to failure of their reutilization, or disposal. Similarly, depletion of phospholipids during ischemia may be due to the inability of cells to reconstitute the lipid following degradation. Regardless of the mechanism, the depletion of phospholipids and accumulation of lipid breakdown products which occur during ischemia may be responsible for membrane damage. In partial agreement with this view, the addition of unesterified, unsaturated fatty acids to primary cultures of proximal tubule cells was shown to result in plasma membrane blebbing and cell death.

Altérations lipidiques induites par l'ischémie rénale: Un facteur pathogène pour les lésions membranaires. Les lipides de la corticale et de la couche externe de la médullaire externe rénales ont été analysés chez des rats au cours d'une ischémie, et 2 heures après recirculation sanguine. Après 15 minutes d'ischémie, il existait des élévations marquées des acides gras libres (FFA) et du diacylglycérol (DG), qui augmentaient encore à 60 minutes. Les élévations en pourcentage étaient plus fortes pour les FFA polyinsaturés. Ces élévations s'accompagnaient d'altérations des phospholipides (PL): augmentation de la lysophosphatidylcholine (LCP) à 15 minutes, de l'acide phosphatidique à 15 et 60 minutes, et baisses de la phosphatidylcholine et du phosphatidylinositol à 60 minutes. Le triacylglycerol (TG) diminuait seulement modérément à 60 minutes, et de façon insuffisante pour rendre compte des élévations de FFA et de DG. Deux heures après 15 minutes d'ischémie, LPC est retournée aux niveaux contrôles, et les autres PL étaient normaux à l'exception du phosphatidylinositol qui était diminué, et de l'acide phosphatidique qui restait élevé. Les FFA et DG approchaient ou atteignaient les valeurs contrôles. Deux heures après 60 minutes d'ischémie, les LPC, FFA, DGs et l'acide phosphatidique restaient élevés; la phosphatidylcholine et le phosphatidylinositol restaient bas. Des lésions histologiques ont été observées au bout de 2 et 24 heures après recirculation sanguine uniquement dans les reins altérés par 60 minutes d'ischémie. Ainsi, une atteinte ischémique irréversible est corrélée à des anomalies persistantes du métabolisme de la phosphatidylcholine, et à des élévations persistantes des FFA, LPC, et DG. On ne sait pas si les lipides se dégradent à des vitesses normales ou élevées au cours de l'ischémie. Dans ce contexte, l'accumulation de produits de dégradation des lipides dans les cellules ischémiques pourrait résulter d'un trouble de leur réutilisation ou de leur élimination. De même, la depletion en phospholipides lors de l'ischémie pourrait résulter d'une incapacité des cellules à reconstituer les lipides après leur dégradation. Quel qu'en soit le mécanisme, la depletion en phospholipides et l'accumulation de produits de dégradation des lipides qui surviennent pendant l'ischémie pourraient être responsables d'une altération membranaire. En accord partiel avec cette idée, l'addition des les acides gras non estérifiés et non saturés à les cultures primaires des cellules tubulaires proximales a été montré résulter dans de bulles dans la membrane plasmique et la mort des cellules.

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