Renal proteinases and kidney hypertrophy in experimental diabetes

Schaefer, Liliana; Schaefer, Roland M.; Li, Hong; Teschner, Markus; Heidland, A.

doi:10.1007/bf00403374

Cited by 42 publications

(8 citation statements)

References 32 publications

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“…Analysing the mechanisms by which MMPs may be altered in DN, data suggest that inflammatory pathways may regulate MMPs expression, however some MMPs may also modulate the expression of inflammatory mediators [80]. It has been reported that insulin-like growth factor 1 (ILGF-1) decreases MMP expression [81][82][83]. TGF-β has shown to upregulate MMP-2 [84].…”

Section: Mmps In Experimental Diabetic Nephropathymentioning

confidence: 99%

Matrix Metalloproteinases in Diabetic Kidney Disease

García-Fernández

Jacobs-Cachá

Mora-Gutiérrez

et al. 2020

JCM

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Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effect.

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Section: Mmps In Experimental Diabetic Nephropathymentioning

confidence: 99%

Matrix Metalloproteinases in Diabetic Kidney Disease

García-Fernández

Jacobs-Cachá

Mora-Gutiérrez

et al. 2020

JCM

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“…In the control rats (Figure 1a) there was severe degradation of [$H]albumin in the urine to peptides with molecular masses 10 kDa. Only small quantities of albumin were retained in its monomer form (peak corresponding to fractions [33][34][35][36][37]. The percentage monomer [$H]albumin is 4p2% (n l 6) as calculated from the area under the peak corresponding to the position of the ultra-pure monomer-labelled albumin which eluted at fractions 33-38 as shown by the dashed line in Figure 1a.…”

Section: Analysis Of the Degree Of Degradation Of Excreted Albumin Inmentioning

confidence: 99%

Alterations in renal degradation of albumin in early experimental diabetes in the rat: a new factor in the mechanism of albuminuria

et al. 1998

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1. Albumin is normally excreted as a mixture of intact protein and fragments that are produced during renal passage. The purpose of this study was to investigate the ratio of intact versus degraded forms of excreted albumin to ascertain whether changes in this ratio could account for the apparent increase in albumin excretion seen in diabetes, as measured by standard radioimmunoassay techniques. 2. Four-week male Sprague-Dawley rats with streptozotocin-induced diabetes and age-matched control rats were intravenously injected with [3H]albumin. Urine collected over 2 h was analysed by size exclusion chromatography and radioimmunoassay. A standard radioimmunoassay found a 7-fold increase in albumin excretion rate in diabetic rats, whereas there was only a 2-fold increase in albumin excretion (intact plus fragments). Urine analysed by size exclusion chromatography showed severe degradation for control rats (% monomer=4+/-2%); in diabetic rats there was a significant amount of monomer albumin excreted, along with moderately degraded and heavily degraded albumin (% monomer=17+/-5%). 3. This study has shown that the radioimmunoassay, which specifically detects intact albumin, considerably underestimates the amount of total urinary albumin which consists of intact and degraded material. The increase in albumin excretion rate observed in diabetes as measured by radioimmunoassay is mainly due to a change in the amount of intact albumin excreted and this is specifically due to the inhibition of albumin degradation at a post-glomerular site and not due to the onset of any type of glomerular 'shunt' pathway.

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“…While some have suggested increased ECM synthesis [7], others have implicated decreased breakdown [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

Elevated ε-(γ-Glutamyl)lysine in Human Diabetic Nephropathy Results from Increased Expression and Cellular Release of Tissue Transglutaminase

et al. 2004

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Introduction: Diabetic nephropathy (DN) is the leading cause of chronic kidney failure, however the mechanisms underlying the characteristic expansion of the extracellular matrix (ECM) in diabetic kidneys remain controversial and unclear. In non-diabetic kidney scarring the protein crosslinking enzyme tissue transglutaminase (tTg) has been implicated in this process by the formation of increased Ε-(γ-glutamyl)lysine bonds between ECM components in both experimental and human disease. Studies in db⁺/db⁺ diabetic mice and in streptozotocin-treated rats have suggested a similar mechanism, although the relevance of this to human disease has not been addressed. Methods: We have undertaken a retrospective analysis of renal biopsies from 16 DN patients with type 2 diabetes mellitus using an immunohistochemical and immunofluorescence approach, with tTg and Ε-(γ-glutamyl)lysine crosslink quantified by confocal microscopy. Results: Immunofluorescent analysis of human biopsies (confocal microscopy) showed increases in levels of tTg (+1,266%, p < 0.001) and Ε-(γ-glutamyl)lysine (+486%, p < 0.001) in kidneys with DN compared to normal. Changes were predominantly in the extracellular periglomerular and peritubular areas. tTg staining correlated with Ε-(γ-glutamyl)lysine (r = 0.615, p < 0.01) and renal scarring (Masson’s trichrome, r = 0.728, p < 0.001). Significant changes in Ε-(γ-glutamyl)lysine were also noted intracellularly in some (≤5%) tubular epithelial cells. This is consistent with cells undergoing a novel transglutaminase-mediated cell death process in response to Ca²⁺ influx and subsequent activation of intracellular tTg. Conclusion: Changes in tTg and Ε-(γ-glutamyl)lysine occur in human DN. Cellular export of tTg may therefore be a factor in the perpetuation of DN by crosslinking and stabilisation of the ECM, while intracellular activation may lead to cell death contributing towards tubular atrophy.

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Renal proteinases and kidney hypertrophy in experimental diabetes

Cited by 42 publications

References 32 publications

Matrix Metalloproteinases in Diabetic Kidney Disease

Matrix Metalloproteinases in Diabetic Kidney Disease

Alterations in renal degradation of albumin in early experimental diabetes in the rat: a new factor in the mechanism of albuminuria

Elevated ε-(γ-Glutamyl)lysine in Human Diabetic Nephropathy Results from Increased Expression and Cellular Release of Tissue Transglutaminase

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