Effects of diabetes and hypertension on macrophage infiltration and matrix expansion in the rat kidney

Hartner, Andrea; Veelken, Roland; Wittmann, Michael; Cordasic, Nada; Hilgers, Karl F.

doi:10.1186/1471-2369-6-6

Cited by 37 publications

(29 citation statements)

References 23 publications

(39 reference statements)

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“…We also found renal macrophage infiltration (8) and matrix expansion (10) in STZ-diabetic in TGR, but our results did not fully confirm those of Kelly and colleagues (16,17,27,37). In our hands, the effects of STZ diabetes added rather little to those of ANG II-dependent hypertension (10).…”

contrasting

confidence: 41%

“…This group of authors then investigated the role of many potential progression factors in this model, including the RAS (27), advanced glycation products (37), and macrophage infiltration (17). We also found renal macrophage infiltration (8) and matrix expansion (10) in STZ-diabetic in TGR, but our results did not fully confirm those of Kelly and colleagues (16,17,27,37). In our hands, the effects of STZ diabetes added rather little to those of ANG II-dependent hypertension (10).…”

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confidence: 99%

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Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes

Hartner¹,

Cordasic²,

Klanke³

et al. 2007

American Journal of Physiology-Renal Physiology

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Hartner A, Cordasic N, Klanke B, Wittmann M, Veelken R, Hilgers KF. Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes. Am J Physiol Renal Physiol 292: F820 -F827, 2007. First published October 3, 2006; doi:10.1152/ajprenal.00088.2006.-Induction of streptozotocin (STZ) diabetes in hypertensive rats transgenic for the mouse ren-2 gene (TGR) has been described as a model of progressive diabetic nephropathy. We investigated the long-term course of STZ diabetes in TGR and appropriate Sprague-Dawley control rats (SD) and tested the role of angiotensin-dependent hypertension by treating rats with the angiotensin II type 1 receptor blocker losartan (1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) via osmotic minipumps. Five weeks after STZ injection, diabetes developed in TGR and SD. Urinary albumin excretion was increased by diabetes and, to a much higher degree, by hypertension. The effects of hypertension and diabetes were not additive, and only the effects of hypertension were ameliorated by losartan. A similar pattern was observed for cell proliferation and macrophage infiltration in the kidney. In contrast, the effects of hypertension and diabetes on glomerular collagen IV accumulation were additive 5 wk after STZ injection. In a long-term study for 20 wk after STZ, survival was better in STZ-treated TGR than in normoglycemic TGR, whereas all SD survived. Impaired creatinine clearance and increased macrophage infiltration as well as glomerular and interstitial matrix deposition were prominent in TGR compared with SD, regardless of the presence or absence of diabetes. In conclusion, STZ diabetes in TGR may be useful to study glomerular and interstitial matrix deposition early in the course of diabetes. However, the long-term course of this animal model resembles severe hypertensive nephrosclerosis, rather than progressive diabetic nephropathy.angiotensin; nephrosclerosis; macrophages; glomerulosclerosis DIABETIC NEPHROPATHY is the most common cause of end-stage renal failure in developed countries, and its incidence continues to rise (32). In most patients with diabetic nephropathy, hypertension is present and contributes significantly to the progression of renal failure in diabetes (32). Studies in diabetic rats as well as in human volunteers with hyperglycemia have indicated that activation of the intrarenal renin-angiotensin system (RAS) plays a key role in the development of the hemodynamic abnormalities in early diabetic nephropathy (1, 13). Angiotensin (ANG) II contributes to systemic and glomerular capillary hypertension in diabetic nephropathy (1) and may exert additional nonhemodynamic effects such as promotion of inflammation and fibrosis (39). The role of ANG II in the development and progression of diabetic nephropathy is supported by clinical trials with ANG II antagonists (22, 30).There is a long-standing debate as to what extent the available rodent models represent human diabetic nephropathy, in particular nephropathy of patients with type 2 diabetes (4, 15)....

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confidence: 41%

mentioning

confidence: 99%

Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes

Hartner¹,

Cordasic²,

Klanke³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…26 The balance between these two processes determines the number of cells in the glomerulus and the outcome of the inflammatory process. Thus, in our current experiment (a model with very little glomerular cellular immigration 28 ), mesangial cells expressing Hic-5 are able to produce collagen I, and to undergo proliferation, before other factors of cell stress trigger apoptosis, 26 although overall glomerular cell number increases. Interestingly, mesangial cells attached to collagen IV with forced expression of Hic-5 show increased Glomerulosclerosis, collagen I, and Hic-5 N Hornigold et al susceptibility to apoptosis compared with wild type.…”

Section: Discussionmentioning

confidence: 60%

Inhibition of collagen I accumulation reduces glomerulosclerosis by a Hic-5-dependent mechanism in experimental diabetic nephropathy

Hornigold

Johnson

Huang

et al. 2013

Laboratory Investigation

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Glomerulosclerosis of any cause is characterized by loss of functional glomerular cells and deposition of excessive amounts of interstitial collagens including collagen I. We have previously reported that mesangial cell attachment to collagen I leads to upregulation of Hic-5 in vitro, which mediates mesangial cell apoptosis. Furthermore, glomerular Hic-5 expression was increased during the progression of experimental glomerulosclerosis. We hypothesized that reducing collagen I accumulation in glomerulosclerosis would in turn lower Hic-5 expression, reducing mesangial cell apoptosis, and thus maintaining glomerular integrity. We examined archive renal tissue from rats undergoing experimental diabetic glomerulosclerosis, treated with the transglutaminase-2 inhibitor NTU281. Untreated animals exhibited increased glomerular collagen I accumulation, associated with increased glomerular Hic-5 expression, apoptosis, and mesangial myofibroblast transdifferentiation characterized by a-smooth muscle actin (a-SMA) expression. NTU281 treatment reduced glomerular collagen I accumulation, Hic-5 and a-SMA expression, and apoptosis. Proteinurea and serum creatinine levels were significantly reduced in animals with reduced Hic-5 expression. In vitro studies of Hic-5 knockdown or overexpression show that mesangial cell apoptosis and expression of both a-SMA and collagen I are Hic-5 dependent. Together, these data suggest that there exists, in vitro and in vivo, a positive feedback loop whereby increased levels of collagen I lead to increased mesangial Hic-5 expression favoring not only increased apoptosis, but also mesangial myofibroblast transdifferentiation and increased collagen I expression. Prevention of collagen I accumulation interrupts this Hic-5-dependent positive feedback loop, preserving glomerular architecture, cellular phenotype, and function.

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“…The act of MCP-1 binding to the CCR2 receptor induces infiltration of inflammatory cells and proliferation of resident glomerular cells, such as epithelial and endothelial cells (Kato et al, 1999;Viedt et al, 2002). In addition, glomerular podocytes are the major glomerular cells that express MCP-1 in various proteinuric conditions, including diabetic and membranous nephropathies (Hartner et al, 2005;Prodjosudjadi et al, 1995). Blockade or loss of MCP-1 has been shown to provide renoprotective effects in experimental diabetic nephropathy (Chow et al, 2006;Kanamori et al, 2007), which suggests an influential role of the MCP-1/CCR2 pathway for the inflammatory process in diabetic injury.…”

Section: Role Of the Mcp-1/ccr2 Pathwaymentioning

confidence: 99%

The Role of Adipose Tissue in Diabetic Kidney Disease

Kang¹,

Joo²,

Hyun³

et al. 2011

Role of the Adipocyte in Development of Type 2 Diabetes

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Effects of diabetes and hypertension on macrophage infiltration and matrix expansion in the rat kidney

Cited by 37 publications

References 23 publications

Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes

Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes

Inhibition of collagen I accumulation reduces glomerulosclerosis by a Hic-5-dependent mechanism in experimental diabetic nephropathy

The Role of Adipose Tissue in Diabetic Kidney Disease

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