Bradykinin and Renal Fibrosis

Bascands, Jean-Loup; Schanstra, Joost P.

doi:10.1097/01.asn.0000143721.71748.30

Cited by 11 publications

(11 citation statements)

References 31 publications

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“…caspases, intrinsic and extrinsic death pathway molecules, inhibitors of cyclin-dependent kinases p27 and p21, reactive oxygen species, and catalase) , the regulation of epithelial-mesenchymal transformation (hepatocyte growth factor, bone morphogenic protein 7, TGFβ-1, HIF-α and nestin) [40][41][42][43], hypoxic injury response (HIF-α) [44,45], cytokines and growth factors (TGFβ-1, EGF, PDGF-C, VEGF, IGF-1, connective tissue growth factor and TNF-α) [3,13,14,20,22,31,36,37,[46][47][48][49], and chemokines and chemoattractants (MCP-1, osteopontin, IL-1, ICAM-1, VCAM-1, angiotensin II and selectins) [13,[50][51][52][53][54][55][56][57][58]. This listing, impressive as it may appear, is by no means complete.…”

Section: Tubular Changesmentioning

confidence: 99%

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Obstructive Uropathy

Truong¹,

Gaber

Eknoyan

2011

Contributions to Nephrology

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Chronic tubulointerstitial nephritis (TIN), characterized by tubular atrophy, interstitial fibrosis and inflammation, is a major prognostic determinant of chronic kidney disease, regardless of the original cause of the kidney disease. Understanding the pathogenesis of TIN has been hampered by the lack of an adequate experimental model. However, the demonstration that the renal lesions of obstructive uropathy induced by experimental urinary obstruction (UO) has provided an excellent model to study the pathogenesis of TIN in general and especially congenital obstructive nephropathy, the most common cause of pediatric end-stage renal disease. Since relief of experimental UO is technically possible, this model is particularly useful for studying the potential reversibility of TIN. Experimental UO is usually created by the unilateral ligation of a ureter. This induces progressive tubular epithelial cell injury, including apoptosis, proliferation, loss of differentiation and atrophy; interstitial inflammatory cell infiltrates composed predominantly of macrophages and T cells; and interstitial fibrosis characterized by an increase and activation of interstitial fibroblasts, deposition of extracellular matrix proteins and loss of peritubular capillaries. These changes collectively lead to progressive scarring and the loss of renal parenchyma and kidney function. The glomeruli and large blood vessels remain either normal or show mild changes later in the course of the disease. In addition to TIN, congenital obstructive nephropathy causes marked derangement of renal and glomerular development. Relief of UO does not seem to reverse TIN. In fact, the renal lesions of obstructive uropathy not only persist, but also progress long after UO is relieved in both adult and neonatal rats. The pathogenesis of UO-induced TIN has been well studied, at least in part because of the ready application of this model to mice, in which genetic manipulation including gene deletion or transfection of putative pathogenic molecules is technically feasible. Experimental UO immediately induces mechanical stretching of tubular epithelial cells and activates the renin-angiotensin system, leading to profound changes of the cells, including neo-expression of a large number of molecules which control cell cycle (e.g. caspases, intrinsic and extrinsic death pathway molecules, inhibitors of cyclin-dependent kinases p27 and p21, reactive oxygen species, and catalase), hypoxic response (HIF- α), epithelial-mesenchymal transformation (e.g. hepatocyte growth factor, bone morphogenic protein 7 and nestin), and the upregulation of cytokines and growth factors (e.g. TGFβ-1, EGF, PDGF, VEGF and TNF-α) as well as chemokines (MCP-1, osteopontin, IL-1, ICAM-1, VCAM-1 and selectins). Inflammatory cells are recruited immediately after UO, probably under the effect of the renin-angiotensin system and later by tubular cell-derived chemokines. Several chemokines and their receptors are also expressed by the infiltrating inflammatory cells, thereby augmenting the recruitm...

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Section: Tubular Changesmentioning

confidence: 99%

“…angiotensin II) and vasodilators (e.g. prostaglandin, thromboxane), in favor of the former, leading to acute renal ischemia and tissue hypoxia [4,13,[56][57][58]. UO also induces mechanical stretching of tubular cells [3,13,28,29].…”

Section: Pathogenesis Of Uo-induced Tinmentioning

confidence: 99%

Obstructive Uropathy

Truong¹,

Gaber

Eknoyan

2011

Contributions to Nephrology

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“…A hallmark of end-stage renal disease (ESRD) is the appearance of tubulointerstitial fibrosis, and this has been shown to be associated with a poor long-term prognosis [30]. Some reports showed that the renal protective effect of ACEI was blocked by BK-B2 receptor antagonist, and this was also accompanied by attenuated plasminogen activator inhibitor-1 (PAI-1) expression and an increase in plasmin activity, suggesting increased extracellular matrix degradation [28,29]. ACE is also a kininase, and BK levels increase after ACE inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…This difference appeared to be mediated by bradykinin (BK), which contributes to efferent arteriolar dilatation and a desirable reduction in intraglomerular pressure [22,27]. In addition to the relief of intraglomerular hypertension, it was reported that ACEI had the effect of a halting or reversing renal tubulointerstitial fibrosis [28,29]. A hallmark of end-stage renal disease (ESRD) is the appearance of tubulointerstitial fibrosis, and this has been shown to be associated with a poor long-term prognosis [30].…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of the rennin–angiotensin system versus maximal recommended dose of angiotensin II receptor blockade in chronic glomerulonephritis

et al. 2008

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“…A number of renal hormones-such as epidermal growth factor (EGF) and aldosterone-may also influence glomerular, tubular and interstitial fibrosis [21]. From a therapeutic point of view, the role of angiotensin-converting-enzyme inhibition and angiotensinreceptor blockade together versus either pharmacologic agent alone needs to be examined at a cellular/signaling level [22].…”

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confidence: 99%

The future of pediatric nephrology

Chesney

2005

Pediatr Nephrol

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The delineation of renal disease in children dates to the 1880s with descriptions of Henoch's purpura, bladder exstrophy, renal rickets and nephritis. The discipline of pediatric nephrology mainly emerged during the 20th century in response to problems in fluid and electrolyte balance, characterization of the nephrotic syndrome, use of renal biopsy, antibiotic therapy of urinary tract infections, dialysis and transplantation in children, growth problems associated with chronic renal failure, detection and therapy of hypertension, and the creation of both national and international pediatric nephrology societies and a journal now in its 18th year. The development of molecular and cell biology, genetic and genomic techniques and bioinformatics methods underlie many future directions. We should anticipate further elucidation of single gene disorders, of complex trait analysis of disorders, such as diabetic nephropathy and hypertension, the interplay of developmental genes and gene products and interactions within the podocyte. Specific therapies directed against inflammation, vascular damage, cyst development, the ravages of proteinuria and graft rejection (or induction leading to tolerance) will be developed. Stem cell therapies may replace lost renal mass, even of specific nephron sites. Novel therapies will also modulate the cell cycle, tyrosine kinase signaling and apoptosis. In addition, drugs will be specifically tested in children for many renal conditions. Larger and more specialized registries will be developed; epidemiologic studies and exploration of large data sets will lead to clinical guidelines that are evidenced-based. There is a need for more careful measurement of glomerular filtration rate (GFR), proteinuria and cytokines, and a fuller appreciation of the nutritional and hormonal role of the kidney. Finally, the antecedents of adult renal disease and the need to intervene in a proactive fashion will be realized. Despite these impressive advances in care, the greatest challenges will be in providing children with renal disease access to well-trained pediatric nephrologists, especially in Asia (1 billion children), Africa, Central and South America, and in immigrant and refugee populations. Included in this challenge is the capacity to have affordable access to use of contemporary techniques, and effective medications and prevention strategies. The International Pediatric Nephrology Association (IPNA), its journal, and pediatric advocates will need to use their energies to take on these challenges.

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Bradykinin and Renal Fibrosis

Cited by 11 publications

References 31 publications

Obstructive Uropathy

Obstructive Uropathy

Dual blockade of the rennin–angiotensin system versus maximal recommended dose of angiotensin II receptor blockade in chronic glomerulonephritis

The future of pediatric nephrology

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