Renal proteinases and kidney hypertrophy in experimental diabetes

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

doi:10.1007/s001250050148

Cited by 15 publications

(16 citation statements)

References 11 publications

(12 reference statements)

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“…Increased cathepsin L gene expression has been found in wasting skeletal muscle of septic rats (25), whereas decreased cathepsin L gene expression and enzyme activity has been reported in mesangial cells cultured with glucose (26). Further, decreased cathepsin L enzyme activity has been reported in hypertrophied kidneys of streptozotocin-induced diabetic rats (27,28). In keeping with this, we observed an inverse correlation between muscle cathepsin L mRNA expression and plasma glucose levels in mice.…”

Section: Discussionsupporting

confidence: 84%

“…This defect is most likely the consequence rather than the cause of the diabetic state, because the impaired postclamp cathepsin L gene expression was seen only in the diabetic but not in the nondiabetic monozygotic co-twin. In keeping with this, decreased cathepsin B and L activity in hypertrophied kidneys of streptozotocin-treated diabetic animals can be normalized by insulin treatment (27,28). Direct evidence is lacking for the effect of glucose on cathepsin L gene expression in muscle.…”

Section: Discussionmentioning

confidence: 97%

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Impaired Cathepsin L Gene Expression in Skeletal Muscle Is Associated With Type 2 Diabetes

Huang

Vaag²,

Carlsson

et al. 2003

Diabetes

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To identify abnormally expressed genes associated with muscle insulin resistance or type 2 diabetes, we screened the mRNA populations using cDNA differential display combined with relative RT-PCR analysis from muscle biopsies of diabetes-prone C57BL/6J and diabetes-resistant NMRI mice fed with a high-fat or normal diet for 3 or 15 months. Six abnormally expressed genes were isolated from the mice after a 3-month fat feeding; one of them was cathepsin L. No significant difference in mRNA levels of these genes was observed between fatand normal-diet conditions in either strains. However, cathepsin L mRNA levels in muscle were higher in normal diet-fed C57BL/6J mice compared with normal diet-fed NMRI mice at 3 months (0.72 ؎ 0.04 vs. 0.51 ؎ 0.04 relative units, P < 0.01, n ‫؍‬ 8 -10) and at 15 months (0.41 ؎ 0.05 vs. 0.27 ؎ 0.04 relative units, P ‫؍‬ 0.01, n ‫؍‬ 9 -10). Further, cathepsin L mRNA levels in muscle correlated inversely with plasma glucose in both strains regardless of diets at 3 (r ‫؍‬ ؊0.49, P < 0.01, n ‫؍‬ 31) and 15 (r ‫؍‬ ؊0.42, P ‫؍‬ 0.007, n ‫؍‬ 39) months. To study whether cathepsin L plays a role in human diabetes, we measured cathepsin L mRNA levels in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and from 12 control subjects. Basal cathepsin L mRNA levels were not significantly different between the study groups. Insulin infusion increased cathepsin L mRNA levels in control subjects from 1.03 ؎ 0.30 to 1.90 ؎ 0.32 relative units (P ‫؍‬ 0.03). Postclamp cathepsin L mRNA levels were lower in diabetic twins but similar in nondiabetic twins compared with control subjects (0.66 ؎ 0.22, 1.16 ؎ 0.18 vs. 1.38 ؎ 0.21 relative units, P < 0.02, NS, respectively). Further, postclamp cathepsin L mRNA levels were correlated with insulin-mediated glucose uptake (r ‫؍‬ 0.37, P ‫؍‬ 0.03), particularly, with glucose oxidation (r ‫؍‬ 0.37, P ‫؍‬ 0.03), and fasting glucose concentrations (r ‫؍‬ ؊0.45, P < 0.01) across all three study groups. In conclusion, muscle cathepsin L gene expression is increased in diabetes-prone mice and related to glucose tolerance. In humans, insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism. Diabetes 52:2411-2418, 2003 I nsulin resistance can be induced by high-fat intake in animals and humans (1-4) and is seen at the levels of whole-body and skeletal muscle (4,5). The degree of fat-induced insulin resistance varies according to different genetic backgrounds in humans (6) and in experimental animals (7-10). The C57BL/6J mouse is genetically prone to develop insulin resistance and diabetes. When challenged with a high-fat diet, the C57BL/6J mouse shows elevated plasma insulin and glucose levels compared with a control mouse strain (8,10). Therefore, strain-specific and fat-responsive genes could contribute to insulin resistance and glucose intolerance in C57BL/6J...

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 97%

Impaired Cathepsin L Gene Expression in Skeletal Muscle Is Associated With Type 2 Diabetes

Huang

Vaag²,

Carlsson

et al. 2003

Diabetes

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“…In parallel to overexpression of TGF-glomerular accumulation of type IV collagen and fibronectin could be detected. This appeared to derive from overproduction of the ECM proteins [74,75] as well as from reduced glomerular proteolytic (gelatinase and cathepsin L+B) activity [76]. In addition to glomerular TGF-overexpression and ECM accumulation, analogous changes were also noted in the renal tubulointerstitium [74,75].…”

Section: Pathogenesis Of Diabetic Glomerulosclerosis: Insights From Amentioning

confidence: 80%

Progression of Diabetic Nephropathy

Phillips

Janssen²,

Floege³

1999

Kidney Blood Press Res

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Nephropathy in patients with type I and II diabetes mellitus is a rapidly increasing problem worldwide. Studies using both glomerular and tubular cells have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial cells, to elevated glucose concentrations, may alter cell proliferation and/or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter cell function. Extension of these studies to the experimental in vivo situation has confirmed most of the in vitro findings. Important insights gained from models of type I diabetes (i.e. streptocotocin–induced diabetes) as well as type II diabetes (i.e. Goto–Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF–β and/or PDGF, occur in streptocotocin–induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type II diabetes does induce morphological changes characteristic of pre–clinical diabetic nephropathy in GK–rats but does not result in albuminuria or progressive renal disease. (3) The demonstration that the association of type II diabetes with hyperlipidemia in obese Zucker rats results in early podocyte damage and subsequent progression to glomerulosclerosis, tubulointerstitial damage, and renal insufficiency. Identification of the mediators involved in the above processes and in particular of the conditions that will determine progression of subclinical morphological changes to overt nephropathy and renal failure will likely result in future novel therapeutic approaches to diabetic nephropathy.

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“…Gelatinolytic enzyme activities were measured fluorometrically in glomeruli from each individual animal (obese: n = 9; lean: n = 9) as we described previously [25]. Denatured rat tail collagen type-1 (gelatin) was used as substrate.…”

Section: Methodsmentioning

confidence: 99%

Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats

et al. 1997

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The obese Zucker rat is an autosomal recessive model of obesity and hyperlipidaemia with many similarities to human non-insulin-dependent diabetes mellitus (NIDDM) [1][2][3]. These metabolic abnormalities precede the development of albuminuria and mesangial matrix expansion followed by segmental glomerulosclerosis [4,5]. Accumulation of matrix components within the mesangium has been demonstrated for collagen IV, fibronectin, laminin and proteoglycans [6][7][8].The turnover of extracellular matrix is dependent on a balance between its synthesis and degradation, and consequently enhanced matrix deposition may be either due to increased synthesis and/or reduced activity of proteinases responsible for the remodelling of the matrix components. Several lines of evidence suggest the involvement of metalloproteinases Diabetologia (1997Diabetologia ( ) 40: 1035Diabetologia ( -1043 Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats Summary The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+ 64 %) and decreased gelatinolytic activity (− 34 %) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 ± 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the a 1 IV collagen chain was 2.1 ± 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1. [Diabetologia (1997[Diabetologia ( ) 40: 1035[Diabetologia ( -1043 Keywords Glomerulosclerosis, matrix metalloproteinase, tissue inhibitor of metalloproteinases, obese Zucker rat.Received: 16 January 1997 and in final revised form: 28 April, 1997Corresponding author: Dr. L. Schaefer, Med. Univ-Poliklinik, Albert-Schweitzer-Str. 33, 48129 Muenster, Germany Abbreviations: MMP, Matrix metalloproteinase; TIMP-1, -2: tissue inhibitor of metalloproteinases-1, -2; TPA, 12-O...

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Renal proteinases and kidney hypertrophy in experimental diabetes

Cited by 15 publications

References 11 publications

Impaired Cathepsin L Gene Expression in Skeletal Muscle Is Associated With Type 2 Diabetes

Impaired Cathepsin L Gene Expression in Skeletal Muscle Is Associated With Type 2 Diabetes

Progression of Diabetic Nephropathy

Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats

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