Schlondorff, D. O. Overview of factors contributing to the pathophysiology of progressive renal disease. Kidney Int. 74, 860-866

Renal Division, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Kidney International (Impact Factor: 8.56). 10/2008; 74(7):860-6. DOI: 10.1038/ki.2008.351
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Some basic premises must be considered when validating hypothesis about progression of renal disease. In an accompanying series of five articles, specific aspects of progression will be reviewed by experts in the field: mechanisms of tissue and matrix remodelling; interstitial fibrosis; the contribution of ischemia and hypoxia; the role and type of the inflammatory infiltrate; and, finally, glomerular sclerosis.

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    • "of loss of nephrons and residual nephron enlargement. Although the agents interfering with the reninangiotensin system such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin AT 1 receptor blockers (ARBs) represent the cornerstone of CKD treatment, their benefit is only partial and new approaches to the renal protection are continuously under investigation (Schlondorff 2008, Maione et al. 2011). "
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    ABSTRACT: Chronic kidney disease (CKD) represents a serious public health problem with increasing prevalence and novel approaches to renal protection are continuously under investigation. The aim of this study was to compare the effect of melatonin and angiotensin II type 2 receptor agonist compound 21 (C21) to angiotensin converting enzyme inhibitor captopril and angiotensin II type 1 receptor blocker olmesartan on animal model of doxorubicin nephrotoxicity. Six groups of 3-month-old male Wistar rats (12 per group) were treated for four weeks. The first group served as a control. The remaining groups were injected with a single dose of doxorubicin (5 mg/kg i.v.) at the same day as administration of either vehicle or captopril (100 mg/kg/day) or olmesartan (10 mg/kg/day) or melatonin (10 mg/kg/day) or C21 (0.3 mg/kg/day) was initiated. After four week treatment, the blood pressure and the level of oxidative stress were enhanced along with reduced glomerular density and increased glomerular size. Captopril, olmesartan and melatonin prevented the doxorubicin-induced increase in systolic blood pressure. All four substances significantly diminished the level of oxidative burden and prevented the reduction of glomerular density and modestly prevented the increase of glomerular size. We conclude that captopril, olmesartan, melatonin and C21 exerted a similar level of renoprotective effects in doxorubicin-induced nephrotoxicity.
    Physiological research / Academia Scientiarum Bohemoslovaca 12/2013; 62 Suppl 1:S181-9. · 1.29 Impact Factor
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    • "Chronic tubulointerstitial inflammation and subsequent fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Many factors contribute to chronic tubulointerstitial inflammation such as proteinuria, hypoxia, oxidant stress and hyperglycemia 1. Increased formation and accumulation of advanced glycation end-products (AGEs) is common in patients with chronic kidney disease (CKD)2. "
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    ABSTRACT: Background/aims: Accumulation of advanced glycation end-products, the well-recognized pro-inflammatory molecules, has been detected in renal tissues including tubules. The aim of the present study was to investigate the role of advanced glycation end-products modified low density lipoprotein (AGE-LDL) in inflammatory cytokines production in human proximal tubular epithelial cells and the underlying mechanism. Methods: The Interleukin-6 (IL-6) and Interleukin-8 (IL-8) production was examined by real-time PCR and ELISA. The expression of Toll-like receptor 2 and 4 (TLR2/4) was detected by flow cytometry and western blot. The interaction of TLR2/4 with AGE-LDL was examined by co-immunoprecipitation assay. The involvement of MyD88 and the downstream molecules in inflammatory cytokines production was examined by siRNA and pharmacologic inhibitors, respectively. Results: AGE-LDL interacted with TLR2 and TLR4. TLR4 siRNA showed stronger inhibition on AGE-LDL-induced IL-6 and IL-8 production than that of TLR2 siRNA. Silencing MyD88, but not TRIF, inhibited AGE-LDL-induced IL-6 and IL-8 production. AGE-LDL stimulation led to phosphorylation of JNK, p38, Akt and the p65 subunit of nuclear factor-κB (NF-κB). Pharmacologic inhibitor of Akt suppressed AGE-LDL-induced activation of NF-κB, but the inhibitor of JNK, p38 or ERK1/2 had no effect. Blocking MyD88, p38, JNK, Akt or NF-κB attenuated AGE-LDL-triggered IL-6 production. Conclusion: AGE-LDL induced IL-6 and IL-8 production via TLR2/4-MyD88-dependent pathway in tubular epithelial cells. These data suggest that activation of TLRs signaling in tubular epithelial cells by AGE-LDL might be a novel mechanism for the tubulointerstitial inflammation.
    International journal of biological sciences 01/2013; 9(1):94-107. DOI:10.7150/ijbs.5246 · 4.51 Impact Factor
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    • "As frequently demonstrated, most obese and diabetic individuals tend to show the same pattern of glomerular hemodynamics as compared to patients and animals with reduced renal mass (preglomerular vasodilation, increased glomerular filtration rate, and filtration fraction). Glomerular filtration rate (GFR) has been shown to be higher in obese individuals, while proteinuria and secondary glomerulosclerosis are now recognized as specific complications of severe obesity [3]. Huge progress has been recently achieved in the study of the endocrine features of adipose tissue, which is able to produce several hormone-like peptides named grouped adipokines. "
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    ABSTRACT: Chronic kidney disease is a major public health problem and characterized by a progressive loss in renal function over a period of months or years as defined by structural or functional abnormalities of the kidney. Several elements contribute to determine a progression of the kidney injury, inducing a worsening of renal damage and accelerating the decline of renal function: obesity and hypertension are two known factors of kidney progression. Remarkable improvements have been recently achieved in the study of the endocrine features of the adipose tissue and have been able to produce hormone-like peptides named adipokines or adipocytokines. Among these adipocytokines, which represent a link between obesity, hypertension, and chronic nephropathy, leptins and adiponectin appear to play an important role. Leptin not only is a prohypertension element (renal progression factor) through the activation sympathetic nervous, but also is able to induce prosclerotic effects directly on the kidney. In contrast, a decline of adiponectin levels has been shown to be related to a picture of hypertension: an endothelial dysfunction has been described as the main pathogenic mechanism responsible for this phenomenon.
    International Journal of Hypertension 12/2012; 2012:943605. DOI:10.1155/2012/943605
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