Fatty acids bound to albumin are filtered through glomeruli, reabsorbed by proximal tubular epithelial cells, and metabolized. Because albumin serves as a carrier, an increase in delivery of fatty acids to the proximal tubule may occur in proteinuric states, possibly leading to toxic effects. At present, the contribution of fatty acids to tubulointerstitial damage and the mechanisms underlying this toxicity remain unclear. We recently found that the transcription factor peroxisome proliferator-activated receptor ␣ (PPAR␣) regulates fatty acid metabolism in proximal tubules, so we tested its role in tubular damage under proteinuric conditions. We induced protein-overload nephropathy in Ppara-null or wildtype (WT) mice by injecting fatty acids bound to BSA. Ppara-null mice exhibited greater renal dysfunction from severe proximal tubular injury than WT mice. Kidneys from Ppara-null mice injected with albumin alone showed little injury. Acute tubular injury was associated with deranged fatty acid homeostasis, increased oxidative stress, increased apoptosis, and activation of NFB signaling. These results suggest a role for fatty acids in proteinuria-associated tubular toxicity, as well as a protective role for PPAR␣. Modulation of PPAR␣ may be a future therapeutic option for tubular toxicity from fatty acids.

Acute respiratory distress syndrome (ARDS) is characterized by a high mortality rate. We have studied whether direct hemoperfusion using a polymyxin B immobilized fiber column (PMX-DHP) is effective for acute lung injury (ALI) and ARDS. Two ALI and eighteen ARDS patients were evaluated, four congestive heart failure (CHF) patients were evaluated as cardiogenic pulmonary edema, and we retrospectively compared the outcome with ten patients with ARDS who had been hospitalized between 1990 and 1998 as the untreated group. PMX-DHP was carried out twice at a rate of 80-100 ml/minute for 2 hours, with a time interval of approximately 24 hours. We monitored systolic blood pressure (BP), diastolic BP, and the PaO(2)/FIO(2) (PF) ratio before and after PMX-DHP treatment. The mortality was classified if patients were alive at day 30 after initiating PMX-DHP. The mortality of ARDS patients was approximately 20%. Systolic BP increased significantly from 106 +/- 20 to 135 +/- 21 and to 125 +/- 20 mmHg on the following day. Diastolic BP increased from 61 +/- 16 to 78 +/- 15, and to 72 +/- 12 mmHg. The PF ratio increased significantly from 125 +/- 54 to 153 +/- 73, and 163 +/- 78 Torr. CHF patients did not reveal improvement of systolic, diastolic BP, and PF ratio after PMX-DHP. Eight of ten patients in the untreated group died through exacerbated ARDS. In ARDS patients, PMX-DHP improved circulatory disturbance and oxygenation despite the underlying diseases. The mortality improved compared with that before induction of PMX-DHP.

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...

A 27-year-old female with short stature and mild hearing loss was diagnosed as having focal-segmental glomerulosclerosis by renal biopsy at our hospital. One year later she developed progressive renal dysfunction and cardiac failure and was admitted again to our hospital for evaluation. Though her only neurological disorder was mild hearing loss, her short stature and elevated lactate and pyruvate values in cerebrospinal fluid suggested mitochondrial cytopathy. A muscle biopsy specimen of the left biceps brachii, using modified Gomori trichrome stain, showed a typical image of ragged-red fibers, and an increased number of giant mitochondria with paracrystalline inclusions were visible by electron microscopy. Mitochondrial DNA from the skeletal muscle showed an A-to-G transition at 3243 of transfer RNA^Leu(UUR), the common point mutation for mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These data confirmed the diagnosis of atypical mitochondrial cytopathy with renal and heart involvement. Mitochondrial cytopathies are often associated with hypertrophic cardiomyopathy but rarely with renal disease. Among the few reported cases with associated renal disease, most included renal tubular disorders; few cases with focal glomerular sclerosis are known. The present case of atypical mitochondrial cytopathy was characterized by a unique clinical course and rare complications with focal-segmental glomerulosclerosis.

Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid (FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPARα), suggesting the benefit of PPARα activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPARα agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPARα agonists without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPARα deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NFκB activation. These effects are common to other fibrates and dependent on PPARα function. Interestingly, however, clofibrate pretreatment also exerted PPARα-independent tubular toxicities in PPARα-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPARα-dependent tubular protective effects outweigh their PPARα-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPARα activator that has a steady serum concentration regardless of kidney dysfunction.