Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes.

The aim of this paper is to study the myocardial damage secondary to long-term streptozotocin-induced type 1 diabetes mellitus (DM1). Normotensive and spontaneously hypertensive rats (SHR) received either streptozotocin injections or vehicle. After 22 or 6 wk, DM1, SHR, DM1/SHR, and control rats were killed, and the left ventricles studied by histology, quantitative PCR, Western blot, ELISA, and electromobility shift assay. Cardiomyocyte cultures were also performed. The expression of profibrotic factors, transforming growth factor-beta (TGF-beta1), connective tissue growth factor, and matrix proteins was increased, and the TGF-beta1-linked transcription factors phospho-Smad3/4 and activator protein-1 were activated in the DM1 myocardium. Proapoptotic molecules FasL, Fas, Bax, and cleaved caspase-3 were also augmented. Myocardial injury in long-term hypertension shared these features. In addition, hypertension was associated with activation of NF-kappaB, increased inflammatory cell infiltrate, and expression of the mediators [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, angiotensinogen, and oxidants], which were absent in long-term DM1. At this stage, the combination of DM1 and hypertension resulted in nonsignificant additive effects. Moreover, the coexistence of DM1 blunted the inflammatory response to hypertension. Anti-inflammatory IL-10 and antioxidants were induced in long-term DM1 and DM1/SHR hearts. Myocardial inflammation was, however, observed in the short-term model. In cultured cardiomyocytes, IL-10, TGF-beta1, and catalase blocked the glucose-stimulated expression of proinflammatory genes. Fibrosis and apoptosis are features of long-term myocardial damage in experimental DM1. Associated hypertension does not induce additional changes. Myocardial inflammation is present in hypertension and short-term DM1, but is not a key feature in long-term DM1. Local reduction of proinflammatory factors and expression of anti-inflammatory and antioxidant molecules may underlie this effect.

[Transcriptomics illustrate a deadly TRAIL to diabetic nephropathy]. / La transcriptómica ilustra nuevas vías letales en la nefropatía diabética.

Diabetic nephropathy is the most common cause of endstage renal disease. Approaches targeting angiotensin II significantly delay its progression. However, many patients still need renal replacement therapy. High throughput techniques such as unbiased gene expression profiling and proteomics may identify new therapeutic targets. Cell death is thought to contribute to progressive renal cell depletion in chronic nephropathies. A European collaborative effort recently applied renal biopsy transcriptomics to identify novel mediators of renal cell death in diabetic nephropathy. Twenty-five percent of cell death regulatory genes were upor downregulated in diabetic kidneys. TNF-related apoptosisinducing ligand (TRAIL) and osteoprotegerin had the highest level of expression. In diabetic nephropathy, tubular cells and podocytes express TRAIL. Inflammatory cytokines, including MIF via CD74, upregulate TRAIL. A high glucose environment sensitized renal cells to the lethal effect of TRAIL, while osteoprotegerin is protective. These results suggest that, in addition to glucose levels, inflammation and TRAIL are therapeutic targets in diabetic nephropathy.

La transcriptómica ilustra nuevas vías letales en la nefropatía diabética / No disponible

La nefropatía diabética es la causa más común de enfermedad renal crónica terminal. La modulación terapéutica de la angiotensina II retarda, pero no evita, su progresión. La muerte celular contribuye a la pérdida de masa renal en las nefropatías crónicas. Un consorcio europeo empleó la transcriptómica en biopsias renales para identificar nuevos mediadores implicados en la muerte de la célula renal durante la nefropatía diabética. Un 25% de los genes relacionados con la muerte celular estaban expresados diferencialmente en la nefropatía diabética. TRAIL y osteoprotegerina fueron los genes más sobre expresados, y también estaba aumentado CD74. Las células tubulares y podocitos expresan TRAIL bajo la regulación de citocinas proinflamatorias(MIF vía CD74, TNF). La hiperglucemia sensibiliza a las células renales a la apoptosis inducida por TRAIL, mientras que la osteoprotegerina protege. Estos resultados sugieren que, además de la glucemia, la inflamación y TRAIL pueden ser objetivos terapéuticos en la nefropatía diabética (AU)

Diabetic nephropathy is the most common cause of end stage renal disease. Approaches targeting angiotensin II significantly delay its progression. However, many patients still need renal replacement therapy. High throughput techniques such as unbiased gene expression profiling and proteomics may identify new therapeutic targets. Cell death is thought to contribute to progressive renal cell depletion in chronic nephropathies. A European collaborative effort recently applied renal biopsy transcriptomics to identify novel mediators of renal cell death in diabetic nephropathy. Twenty-five percent of cell death regulatory genes were up or down regulated in diabetic kidneys. TNF-related apoptosis inducing ligand (TRAIL) and osteoprotegerin had the highest-level of expression. In diabetic nephropathy, tubular cells and podocytes express TRAIL. Inflammatory cytokines, including MIF via CD74, up regulate TRAIL. A high glucose environment sensitized renal cells to the lethal effect of TRAIL, while osteoprotegerin is protective. These results suggest that, in addition to glucose levels, inflammation and TRAIL are therapeutic targets in diabetic nephropathy (AU)

Apoptosis: from advances in PD to therapeutic targets in DM

A high glucose concentration is shared by peritoneal dialysis (PD)and diabetes mellitus (DM). High glucose leads to tissue injury indiabetes. Peritoneal dialysis research has emphasized the role of glucose degradation products in tissue injury. Apoptosis induction is one of the mechanisms of tissue injury induced both by glucose and glucose degradation products. We now review the role of apoptosis and its regulation by glucose degradation products in antibacterial defense and loss of renal function in diabetes mellitus and peritoneal dialysis. The pathogenic role of the recently identified glucose degradation product 3,4-di-deoxyglucosone-3-ene (3,4-DGE) is detailed. Available therapeutic strategies include the use of peritoneal dialysis solutions containing alow concentration of glucose degradation products. Based on preclinical results, specific targeting of apoptosis regulatory factor should be explored in the clinical setting (AU)

En la diálisis peritoneal (DP) y la diabetes mellitus (DM)altas concentraciones de glucosa se asocian a daño tisular. La apoptosis es uno de los mecanismos de daño tisular. Los productos de degradación de la glucosa (PDGs) se producen a partir de la glucosa tanto in vivo, en diabéticos, como durante el procesamiento de las soluciones de DP e inducen apoptosis en distintos tipos celulares. La apoptosises un modo activo de muerte celular con control molecular, regulada por moléculas intracelulares y extracelulares que dan lugar a distintas vías pro y antiapoptóticas, susceptibles de manipulación terapéutica. Entre estas se encuentran las caspasas, una familia de protein cisteasas que se comportan como moléculas iniciadoras o efectoras de la apoptosis. Entre los PDGs conocidos, la 3,4 dideoxiglucosona(3,4 DGE) es el principal componente letal de las soluciones de DP. La 3,4 DGE induce apoptosis en leucocitos y células tubulares de riñón. La inhibición de la apoptosis de leucocitos mejora la defensa antibacteriana peritoneal. Proponemos que los PDGs pueden estar implicados en el empeoramiento de la defensa antibacteriana y en lapérdida progresiva de la función renal en pacientes diabéticos y en DP. Entre las posibles estrategias terapéuticas destacamos el empleo de soluciones de DP con baja concentración de PDGs, que podrían disminuir la incidencia y gravedad de las peritonitis así como conservar la función renal residual. Otra posible estrategia seria el empleo de fármacos inhibidores de la apoptosis patológica (AU)

TWEAK, el facilitador del daño renal agudo / No disponible

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Apoptosis: from advances in PD to therapeutic targets in DM.

A high glucose concentration is shared by peritoneal dialysis (PD) and diabetes mellitus (DM). High glucose leads to tissue injury in diabetes. Peritoneal dialysis research has emphasized the role of glucose degradation products in tissue injury. Apoptosis induction is one of the mechanisms of tissue injury induced both by glucose and glucose degradation products. We now review the role of apoptosis and its regulation by glucose degradation products in antibacterial defense and loss of renal function in diabetes mellitus and peritoneal dialysis. The pathogenic role of the recently identified glucose degradation product 3,4-di-deoxyglucosone- 3-ene (3,4-DGE) is detailed. Available therapeutic strategies include the use of peritoneal dialysis solutions containing a low concentration of glucose degradation products. Based on preclinical results, specific targeting of apoptosis regulatory factor should be explored in the clinical setting.

Modulation of renal tubular cell survival: where is the evidence?

Tubular cell loss is prominent both in acute and chronic renal failure. Apoptosis and its regulatory mechanisms contribute to cell number regulation in the kidney. The potential role of apoptosis ranges from induction and progression to repair of renal injury. However, therapeutic interest has focused in preventing the apoptotic loss of tubular cells that leads to acute and chronic renal failure. Death ligands and receptors, such as tumor necrosis factor and Fas ligand, proapoptotic and antiapoptotic Bcl2 family members and caspases have all been shown to participate in apoptosis regulation in the course of renal cell injury. Nevertheless, the precise role of these proteins is unclear, and the participation of most known apoptosis regulatory proteins has not been studied. We now review the role of apoptosis in renal injury, the potential molecular targets of therapeutic intervention, the therapeutic weapons to modulate the activity of these targets and the few examples of therapeutic intervention on apoptosis, with emphasis in acute renal failure.