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1.
Diabetes ; 65(3): 755-67, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26384385

ABSTRACT

Overcoming refractory massive proteinuria remains a clinical and research issue in diabetic nephropathy. This study was designed to investigate the pathogenesis of massive proteinuria in diabetic nephropathy, with a special focus on podocyte autophagy, a system of intracellular degradation that maintains cell and organelle homeostasis, using human tissue samples and animal models. Insufficient podocyte autophagy was observed histologically in patients and rats with diabetes and massive proteinuria accompanied by podocyte loss, but not in those with no or minimal proteinuria. Podocyte-specific autophagy-deficient mice developed podocyte loss and massive proteinuria in a high-fat diet (HFD)-induced diabetic model for inducing minimal proteinuria. Interestingly, huge damaged lysosomes were found in the podocytes of diabetic rats with massive proteinuria and HFD-fed, podocyte-specific autophagy-deficient mice. Furthermore, stimulation of cultured podocytes with sera from patients and rats with diabetes and massive proteinuria impaired autophagy, resulting in lysosome dysfunction and apoptosis. These results suggest that autophagy plays a pivotal role in maintaining lysosome homeostasis in podocytes under diabetic conditions, and that its impairment is involved in the pathogenesis of podocyte loss, leading to massive proteinuria in diabetic nephropathy. These results may contribute to the development of a new therapeutic strategy for advanced diabetic nephropathy.


Subject(s)
Apoptosis , Autophagy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetic Nephropathies/metabolism , Kidney/metabolism , Podocytes/metabolism , Proteinuria/metabolism , Adult , Aged , Animals , Autophagy-Related Protein 5 , Autophagy-Related Protein 7 , Blotting, Western , Cell Line , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/etiology , Diabetic Nephropathies/pathology , Diet, High-Fat , Female , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Intravital Microscopy , Kidney/pathology , Lysosomes/metabolism , Lysosomes/pathology , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microfilament Proteins/metabolism , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Microtubule-Associated Proteins/genetics , Middle Aged , Proteinuria/etiology , Proteinuria/pathology , RNA-Binding Proteins/blood , Rats , Rats, Long-Evans , Severity of Illness Index , Young Adult
2.
Biochim Biophys Acta ; 1842(7): 1097-108, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24726883

ABSTRACT

Podocyte apoptosis is a potent mechanism of proteinuria in diabetic nephropathy. More detailed mechanistic insight into podocyte apoptosis is needed to better understand the pathogenesis of diabetic nephropathy. An elevated level of serum free fatty acid (FFA), as well as hyperglycemia, is a clinical characteristic in diabetes, although its causal role in podocyte apoptosis remains unclear. This study examined the effect of three types of FFAs, saturated, monounsaturated and polyunsaturated FFAs, on podocyte apoptosis. Palmitate, a saturated FFA, induced endoplasmic reticulum (ER) stress-dependent apoptosis in podocytes. Oleate, a monounsaturated FFA, and eicosapentaenoic acid (EPA), an ω-3 polyunsaturated FFA did not induce apoptosis; rather, they antagonized palmitate-induced apoptosis. Palmitate activated mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a nutrient-sensing kinase regulating a wide range of cell biology. Furthermore, inhibition of mTORC1 activity by rapamycin or siRNA for Raptor, a component of mTORC1, ameliorated palmitate-induced ER stress and apoptosis in podocytes. Activity of mTORC1 is regulated by upstream kinases and Rag/Ragulator-dependent recruitment of mTOR onto lysosomal membranes. Palmitate activated mTORC1 by enhancing recruitment of mTOR onto lysosomal membranes, which was inhibited by co-incubation with oleate or EPA. Inhibition of mTOR translocation onto lysosomes by transfection with dominant-negative forms of Rag ameliorated palmitate-induced apoptosis. This study suggests that saturated and unsaturated FFAs have opposite effects on podocyte apoptosis by regulating mTORC1 activity via its translocation onto lysosomal membranes, and the results provide a better understanding of the pathogenesis in diabetic nephropathy and a novel role of mTORC1 in cell apoptosis.


Subject(s)
Apoptosis/physiology , Fatty Acids/metabolism , Lysosomes/metabolism , Multiprotein Complexes/metabolism , Podocytes/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Cell Line , Diabetic Nephropathies/metabolism , Eicosapentaenoic Acid/metabolism , Endoplasmic Reticulum Stress/physiology , Food , HEK293 Cells , Humans , Mechanistic Target of Rapamycin Complex 1 , Mice , Oleic Acid/metabolism , Palmitates/metabolism
3.
Semin Nephrol ; 34(1): 9-16, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24485025

ABSTRACT

Autophagy is a major catabolic pathway by which mammalian cells degrade and recycle macromolecules and organelles. It plays a critical role in removing protein aggregates, as well as damaged or excess organelles, to maintain intracellular homeostasis and to keep cells healthy. The accumulation of damaged proteins and organelles induced by hyperglycemia and other metabolic alterations is strongly associated with the development of diabetic nephropathy. Autophagy is up-regulated under conditions of calorie restriction and environmental stress, such as oxidative stress and hypoxia in proximal tubular cells, and occurs even under normal conditions in podocytes. These findings have led to our hypothesis that autophagy is involved in the pathogenesis of diabetic nephropathy, a hypothesis increasingly supported by experimental evidence. To date, however, the exact role of autophagy in diabetic nephropathy has not been fully revealed. This article therefore reviews recent findings and provides perspectives on the involvement of autophagy in diabetic nephropathy.


Subject(s)
Autophagy/physiology , Diabetic Nephropathies/etiology , Animals , Humans , Kidney Tubules, Proximal/cytology , Mechanistic Target of Rapamycin Complex 1 , Multiprotein Complexes/physiology , Podocytes/physiology , TOR Serine-Threonine Kinases/physiology
4.
J Diabetes Res ; 2013: 193757, 2013.
Article in English | MEDLINE | ID: mdl-24455746

ABSTRACT

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to combat diabetic nephropathy is required. Autophagy is a catabolic process that degrades damaged proteins and organelles in mammalian cells and plays a critical role in maintaining cellular homeostasis. The accumulation of proteins and organelles damaged by hyperglycemia and other diabetes-related metabolic changes is highly associated with the development of diabetic nephropathy. Recent studies have suggested that autophagy activity is altered in both podocytes and proximal tubular cells under diabetic conditions. Autophagy activity is regulated by both nutrient state and intracellular stresses. Under diabetic conditions, an altered nutritional state due to nutrient excess may interfere with the autophagic response stimulated by intracellular stresses, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing the relationships between autophagy and diabetic nephropathy and suggest the therapeutic potential of autophagy in diabetic nephropathy.


Subject(s)
Autophagy/physiology , Diabetic Nephropathies/etiology , Animals , Diabetic Nephropathies/physiopathology , Drug Discovery , Humans , Kidney Tubules, Proximal/physiology , Podocytes/physiology
5.
Biochem Biophys Res Commun ; 417(1): 352-7, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22155234

ABSTRACT

Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins. In insulin resistant adipocytes, various dysfunctional/damaged molecules, organelles, proteins, and end-products accumulate. However, the role of autophagy (in particular, whether autophagy is activated or not) is poorly understood. In this study we found that in adipose tissue of insulin resistant mice and hypertrophic 3T3-L1 adipocytes autophagy was suppressed. Also in hypertrophic adipocytes, autophagy-related gene expression, such as LAMP1, LAMP2, and Atg5 was reduced, whereas gene expression in the inflammatory-related genes, such as MCP-1, IL-6, and IL-1ß was increased. To find out whether suppressed autophagy was linked to inflammation we used the autophagy inhibitor, 3-methyladenine, to inhibit autophagy. Our results suggest that such inhibition leads to an increase in inflammatory gene expression and causes endoplasmic reticulum (ER) stress (which can be attenuated by treatment with the ER stress inhibitor, Tauroursodeoxycholic Acid). Conversely, the levels of inflammatory gene expression were reduced by the activation of autophagy or by the inhibition of ER stress. The results indicate that the suppression of autophagy increases inflammatory responses via ER stress, and also defines a novel role of autophagy as an important regulator of adipocyte inflammation in systemic insulin resistance.


Subject(s)
Adipocytes/pathology , Autophagy , Endoplasmic Reticulum Stress , Inflammation/pathology , 3T3-L1 Cells , Adenine/analogs & derivatives , Adenine/pharmacology , Animals , Gene Expression Regulation , Green Fluorescent Proteins/genetics , Inflammation/genetics , Insulin Resistance , Mice , Mice, Transgenic , Microtubule-Associated Proteins/genetics
6.
Nihon Jinzo Gakkai Shi ; 53(7): 1053-8, 2011.
Article in Japanese | MEDLINE | ID: mdl-22073872

ABSTRACT

A 77-year-old Japanese man was referred to our hospital because of the progression of renal dysfunction. Two months prior to the admission he had been diagnosed with otitis media. Urinalysis showed proteinuria and microscopic hematuria. Blood examination revealed renal dysfunction, hepatitis C virus (HCV)infection and positive myeloperoxidase (MPO)-ANCA. A chest CT revealed small infiltrates in the right middle lobe. The renal biopsy demonstrated crescentic glomerulonephritis with tubulitis. He was diagnosed as having Wegener's granulomatosis according to the American College of Rheumatology classification criteria. Methylprednisolone pulse therapy followed by oral prednisolone improved all of the otitis media, lung infiltrates and renal function. Recently, a high prevalence of ANCA has been reported in patients with HCV. It has also been reported that the prevalence of HCV infection is high in patients with Wegener's granulomatosis. Therefore, our case points to the clinical significance of HCV infection in ANCA-associated systemic vasculitis including Wegener's granulomatosis.


Subject(s)
Antibodies, Antinuclear , Granulomatosis with Polyangiitis/etiology , Granulomatosis with Polyangiitis/immunology , Hepatitis C/complications , Peroxidase/immunology , Aged , Glomerulonephritis/diagnosis , Glomerulonephritis/drug therapy , Glomerulonephritis/etiology , Glomerulonephritis/pathology , Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/drug therapy , Hepatitis C/immunology , Humans , Male , Methylprednisolone/administration & dosage , Otitis Media/complications , Otitis Media/drug therapy , Prednisolone/administration & dosage , Pulse Therapy, Drug , Treatment Outcome
7.
Clin Exp Nephrol ; 15(2): 294-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21225308

ABSTRACT

Diffuse alveolar hemorrhage (DAH) is a rare but fatal complication in patients with systemic lupus erythematosus (SLE). We describe a case of a 74-year-old woman who presented with DAH as an initial presentation of SLE. She also had microscopic polyangiitis clinically manifesting as crescentic glomerulonephritis and purpura with positive myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA). The patient transiently improved when treated with plasma exchange and methylprednisolone pulse therapy; however, she died of recurrent pulmonary hemorrhage and concurrent cryptococcal pneumonia. This case indicates that MPO-ANCA is associated with severe organ involvement such as pulmonary hemorrhage and crescentic glomerulonephritis in SLE.


Subject(s)
Lupus Nephritis/complications , Microscopic Polyangiitis/etiology , Aged , Antibodies, Antineutrophil Cytoplasmic/blood , Fatal Outcome , Female , Hemorrhage/etiology , Humans , Lung Diseases/etiology , Lupus Nephritis/therapy , Methylprednisolone/therapeutic use , Peroxidase/immunology , Plasma Exchange , Pulmonary Alveoli
8.
Case Rep Nephrol ; 2011: 824709, 2011.
Article in English | MEDLINE | ID: mdl-24527238

ABSTRACT

A 21-year-old Japanese male with severe hemophilia A was developed end-stage renal failure. He was placed on combination therapy with peritoneal dialysis (PD) and hemodialysis (HD). Eight months later, he developed a hypertensive cerebral hemorrhage. After emergency surgery, he was managed with PD without HD to avoid cerebral edema. One month later, his renal replacement therapy was switched to HD (three times a week) from PD, since a ventriculoperitoneal shunt catheter was placed to treat his hydrocephalus. HD could be performed safety without anticoagulant agents on condition that factor VIII is given after every HD.

9.
Intern Med ; 49(14): 1401-3, 2010.
Article in English | MEDLINE | ID: mdl-20647656

ABSTRACT

The combined clinical presentation of acute renal failure with pulmonary hemorrhage is known as pulmonary-renal syndrome. We describe a case of an 84-year-old woman who presented with acute renal failure and pulmonary hemorrhage at onset. Renal biopsy and bone marrow aspiration showed cast nephropathy and an abnormal increase in plasma cells, respectively. She was diagnosed with multiple myeloma and successfully treated with plasma exchange and corticosteroids. This case indicates that multiple myeloma should be considered as a cause of pulmonary-renal syndrome.


Subject(s)
Acute Kidney Injury/diagnosis , Hemorrhage/diagnosis , Lung Diseases/diagnosis , Multiple Myeloma/diagnosis , Acute Kidney Injury/complications , Aged, 80 and over , Diagnosis, Differential , Female , Hemorrhage/complications , Humans , Lung Diseases/complications
10.
Rheumatol Int ; 28(12): 1283-4, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18493765

ABSTRACT

We encountered an adult patient with rheumatoid arthritis who developed acute interstitial nephritis associated with an anti-tumor necrosis factor alpha agent, etanercept.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Immunoglobulin G/adverse effects , Nephritis, Interstitial/chemically induced , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Etanercept , Female , Humans , Middle Aged , Receptors, Tumor Necrosis Factor
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