Metabolic fuels along the nephron: Pathways and intracellular mechanisms of interaction

Guder, W. G.; Wagner, Siegfried; Wirthensohn, Gabriele

doi:10.1038/ki.1986.6

Cited by 124 publications

(95 citation statements)

References 19 publications

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“…along the microtubules (21,25). In the present study, starvation was found to enhance the dependence of renal ATP production on fatty acid metabolism, owing to the decrease in serum glucose and carbohydrate metabolite levels ( Figure 6A) (25), the increase in the serum fatty acid levels (26), and the inhibition in the uptake of lactic acid to the proximal tubules by the increased fatty acids (27,28). However, the renal fatty acid ␤-oxidation ability of the PPAR␣-null mice, which was very low in the control state, was neither induced nor activated by starvation ( Figure 6B), resulting in an acute ATP insufficiency ( Figure 6B).…”

Section: Discussionmentioning

confidence: 90%

Identification of Functions of Peroxisome Proliferator-Activated Receptor α in Proximal Tubules

Kamijo¹,

Hora²,

Tanaka³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Peroxisome proliferator-activated receptor ␣ (PPAR␣) is a member of the steroid/nuclear receptor superfamily that is intensively expressed in the kidney, but its physiologic function is unknown. In this study, PPAR␣-null mice were used to help clarify the function. Starved PPAR␣-null mice were found to secrete significantly more quantities of urine albumin than starved wild-type mice. Furthermore, the appearance of giant lysosomes, marked accumulation of albumin, and an impaired ability concerning albumin digestion were found only in proximal tubules of the starved PPAR␣-null mice. These abnormalities were probably derived from ATP insufficiency as a result of the starvation-induced decline of carbohydrate metabolism and a lack of PPAR␣-dependent fatty acid metabolism. It is interesting that these abnormalities disappeared when glucose was administered. Taken together, these findings demonstrate important functions of PPAR␣ in the proximal tubules, the dynamic regulation of the proteindegradation system through maintenance of ATP homeostasis, and emphasize the importance of the fatty acid metabolism in renal physiology.Recently, considerable attention has been paid to the peroxisome proliferator-activated receptor ␣ (PPAR␣), which is known as a member of the steroid/nuclear receptor superfamily (1). According to some studies (2,3), a high level of PPAR␣ is found in the kidney and mainly localizes in the proximal tubules, although its physiologic function has not yet been clarified. Proximal tubular epithelial cells are highly differentiated cells that reabsorb many substances that are essential to the body from glomerular filtrate and secrete several physiologically active compounds. It was suggested that ATP produced in the proximal tubular epithelial cells, which contain a greater density of mitochondria, is necessary for supporting its specific functions and maintaining basic cell functions (4).To elucidate the physiologic role of PPAR␣ in the kidney, we examined the reabsorption process in the proximal tubules, using PPAR␣-null mice. We focused on albumin reabsorption, a typical component of the filtered protein handling, done through efficient receptor-mediated endocytosis in which megalin acts as the main receptor (5-8). The relationship between albumin reabsorption and energy production was also determined, because PPAR␣ is known to play an important role as a potent regulator of mitochondrial energy production in the liver and heart (9,10). In addition, we used starved mice to increase the dependence on fatty acids as an energy fuel source and to reduce the effect of carbohydrate metabolites. Materials and Methods MaterialsAnti-mouse albumin IgG was purchased from Bethyl Laboratories (Montgomery, TX). Anti-rat cathepsin D IgG, ATP, acetyl-CoA, and tripalmitin were from Wako (Osaka, Japan). Anti-Rab5a IgG, antiRab7 IgG, and anti-mouse cathepsin L IgG were from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-LAMP-1 IgG was from American Research Products (Belmont, MA). Anti-megalin polyclonal ant...

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Section: Discussionmentioning

confidence: 90%

Identification of Functions of Peroxisome Proliferator-Activated Receptor α in Proximal Tubules

Kamijo¹,

Hora²,

Tanaka³

et al. 2002

Journal of the American Society of Nephrology

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“…There, the increases of acyl-CoA occur predominantly in the mitochondria and are associated with inhibition ofthe mitochondrial adenine nucleotide translocase (53). Proximal tubules use fatty acids as a main energy source (54,55). In the isolated tubule preparation, butyrate serves as a short chain fatty acid that is highly effective for this purpose (55).…”

Section: Discussionmentioning

confidence: 99%

Cytoprotective effects of glycine and glutathione against hypoxic injury to renal tubules.

Weinberg¹,

Davis²,

Abarzua³

et al. 1987

J. Clin. Invest.

260

141

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Roles for both the tripeptide, GSH, and individual amino acids in modifying the cellular response to oxygen deprivation-induced injury have been suggested by prior work in kidney and other tissues, but the precise interrelationships have not been clearly defined. We have studied the effects of GSH, its component amino acids, and related compounds on the behavior of isolated renal proximal tubules in a well characterized model of hypoxic injury in vitro. GSH, the combination of cysteine, glutamate, and glycine and glycine alone, when present in the medium during 30 min hypoxia, a duration sufficient to produce extensive irreversible injury in untreated tubules, were protective. Significant effects were detected at 0.25 mM concentrations of the reagents, and protection was nearly complete at concentrations of 1 mM and above. Glutamate and cysteine alone were not protective. The exogenous GSH added to the tubule suspensions was rapidly degraded to its component amino acids. Treatment of tubules with GSH or cysteine, but not glycine, increased intracellular GSH levels. Oxidized GSH was protective. Serine, N-(2-mercaptopropionyl)-glycine, and a panel of agents known to modify injury produced by reactive oxygen metabolites were without benefit. These observations identify a novel and potent action of glycine to modify the course of hypoxic renal tubular cell injury. This effect is independent of changes in cellular GSH metabolism and appears to be unrelated to alterations of cell thiols or reactive oxygen metabolites. Further elucidation of its mechanism may provide insight into both the basic pathophysiology of oxygen deprivation-induced cell injury and a practical way to ameliorate it.

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“…The kidney plays a central role in the excretion of waste material from the body while simultaneously maintaining plasma metabolite homeostasis. Within the renal cortex, the proximal tubular cells (PTCs) are known to have highly active lipid and glucose metabolism, because these cells need energy to reabsorb salts, water, and metabolic substances through active transport processes (29)(30)(31). Therefore, it is likely that LXR may be involved in the regulation of lipid and glucose metabolism within these cells.…”

mentioning

confidence: 99%

Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

Wang

Moser

Shigenaga

et al. 2005

Journal of Lipid Research

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Infection and inflammation induce the acute-phase response (APR), which leads to dramatic alterations in lipid and lipoprotein metabolism (1, 2). Hypertriglyceridemia (3, 4), decreased high density lipoprotein cholesterol levels (5, 6), enhanced lipolysis, and decreased fatty acid oxidation (7, 8) are some of the changes that are often observed during the APR. These alterations in lipoprotein metabolism are believed to confer immediate protection to the host from further detrimental damage during the acute stage of infection (1, 2). In many instances, these metabolic alterations are attributable to increased or decreased transcription of genes that control lipid metabolism, and they are often induced by proinflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1) (1, 2). Although the underlying mechanisms remain to be identified, we and others have shown that cytokine-induced suppression of many lipid genes during the APR is achieved through the downregulation of type II nuclear hormone receptors (9-13).Several nuclear hormone receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and farnesoid X receptor (FXR), belong to the type II receptor superfamily (14). These receptors bind to DNA as obligate heterodimers with the retinoid X receptor (RXR) (15). Unlike the steroid receptors that shuttle between the cytoplasm and the nucleus, most RXR heterodimers are constitutively in the nucleus. In the absence of ligand, the heterodimers are believed to be bound to DNA and complexed with corepressor proteins. Ligand binding induces a structural change that dissociates the corepressor proteins, recruits the coactivator proteins, and promotes the transcription of target genes (16).Among these nuclear hormone receptors, LXR plays an important role in regulating the transcription of genes responsible for cholesterol metabolism and homeostasis, in-

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Metabolic fuels along the nephron: Pathways and intracellular mechanisms of interaction

Cited by 124 publications

References 19 publications

Identification of Functions of Peroxisome Proliferator-Activated Receptor α in Proximal Tubules

Identification of Functions of Peroxisome Proliferator-Activated Receptor α in Proximal Tubules

Cytoprotective effects of glycine and glutathione against hypoxic injury to renal tubules.

Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

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