Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat

Schaefer, Liliana; Han, Xiao; Gertz, Norbert; Häfner, Christine; Meier, Karin; Matzkies, F; Schaefer, Roland M.

doi:10.1038/ki.1996.10

Cited by 61 publications

(31 citation statements)

References 36 publications

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“…MMPs, a group of zinc-dependent enzymes that modulate matrix remodeling and turnover, have been implicated in the pathogenesis of PKD. Increased intrarenal expression of both MMPs and TIMPs have been demonstrated in kidneys of both cpk mice and Han:SPRD-cy rats (90,123,132).…”

Section: Anti-inflammatory Agents and Mmp Inhibitorsmentioning

confidence: 99%

Murine models of polycystic kidney disease: molecular and therapeutic insights

Guay‐Woodford

2003

American Journal of Physiology-Renal Physiology

176

160

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Guay-Woodford, Lisa M. Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285: F1034-F1049, 2003 10.1152/ajprenal. 00195.2003.-Numerous murine (mouse and rat) models of polycystic kidney disease (PKD) have been described in which the mutant phenotype results from a spontaneous mutation or engineering via chemical mutagenesis, transgenic technologies, or gene-specific targeting in mouse orthologs of human PKD genes. These murine phenotypes closely resemble human PKD, with common abnormalities observed in tubular epithelia, the interstitial compartment, and the extracellular matrix of cystic kidneys. In both human and murine PKD, genetic background appears to modulate the renal cystic phenotype. In murine models, these putative modifying effects have been dissected into discrete factors called quantitative trait loci and genetically mapped. Several lines of experimental evidence support the hypothesis that PKD genes and their modifiers may define pathways involved in cystogenesis and PKD progression. Among the various pathway abnormalities described in murine PKD, recent provocative data indicate that structural and/or functional defects in the primary apical cilia of tubular epithelia may play a key role in PKD pathogenesis. This review describes the most widely studied murine models; highlights the data regarding specific gene defects and genetic modifiers; summarizes the data from these models that have advanced our understanding of PKD pathogenesis; and examines the effect of various therapeutic interventions in murine PKD.autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease; polycystic kidney disease quantitative trait loci; polycystic kidney disease therapeutics RENAL TUBULAR CYSTS DEVELOP in several inherited human disorders. Among these, the polycystic kidney diseases (PKD) are one of the leading causes of endstage renal disease in children and adults (31). Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1:1,000 individuals, primarily as the result of mutations in one of two genes, PKD1 or PKD2 (81,(150)(151)(152). In comparison, autosomal recessive polycystic kidney disease (ARPKD) is much less frequent (1: 20,000 live births) and results primarily from mutations in a single gene, PKHD1 (107, 162).The principal pathological manifestations in PKD involve 1) the formation of epithelial-lined cysts throughout the nephron in ADPKD and predominantly in the collecting duct in ARPKD; 2) alterations in cell polarity; and 3) changes in extracellular matrix composition. In addition to the renal cystic disease, ADPKD is associated with cyst formation in other epithelial organs, most notably the liver and pancreas, as well as connective tissue defects, such as intracranial aneurysms, aortic dissection, cardiac valve abnormalities, and abdominal wall hernias (116). In comparison, the ARPKD phenotype is expressed almost exclusively in the kidney and liver, with the latter lesion involving biliary dysgenesis a...

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Section: Anti-inflammatory Agents and Mmp Inhibitorsmentioning

confidence: 99%

Murine models of polycystic kidney disease: molecular and therapeutic insights

Guay‐Woodford

2003

American Journal of Physiology-Renal Physiology

176

160

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“…In this respect, tubular MMP-2 was reduced in an animal model of polycystic kidney disease (21). Therefore, we did not investigate urinary MMP-2 levels in subjects with ADPKD.…”

Section: Untreated Patients Versus Healthy Control Subjects and Versumentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibition but not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis

Lods

Ferrari

Frey

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Equivalent long-term effects on the kidney are attributed to angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB). Nevertheless, it is unknown to which degree effects of these compounds on individual inflammatory mediators, including matrix metalloproteinases (MMP), are comparable. On the basis of structural and functional differences, it was hypothesized that ACEI and ARB differentially regulate MMP activity. In a randomized, prospective crossover trial, the effect of an ACEI (fosinopril; 20 mg/d) and of an ARB (irbesartan; 150 mg/d) on MMP activity was evaluated. Ten hypertensive patients with glomerulonephritis and normal or mildly reduced creatinine clearance were studied. MMP activity and tissue inhibitors of metalloproteinase (TIMP) levels were analyzed in serum and urine: without therapy, with ACEI, with ARB, and with both agents combined. Treatment periods continued for 6 wk separated by periods of 4 wk each without therapy. Untreated patients with glomerulonephritis displayed distinctively higher serum levels of MMP-2 but much lower MMP-1/-8/-9 concentrations compared with healthy control subjects. Immunohistology of MMP-2 and MMP-9 in kidney biopsy specimen was accordingly. However, these patients excreted higher amounts of MMP-2 and MMP-9 in urine than healthy control subjects, possibly reflecting ongoing glomerular inflammation. In patients with glomerulonephritis, ACEI significantly reduced overall MMP serum activity to 25%, whereas ARB did not show any effect. Activities of MMP-1/-2/-8/-9 were also significantly inhibited by fosinopril but not by irbesartan. Levels of TIMP-1/-2 remained unaffected. In conclusion, ACEI and ARB differentially regulate MMP activity, which may ultimately have consequences in certain types of MMP-dependent glomerulonephritis.Glomerular inflammatory diseases represent frequent and often difficult-to-treat causes of end-stage kidney failure. Hypertension and proteinuria are important independent determinants and risk factors for progression of these diseases (1). Therefore, these two conditions are prime targets for the therapy of all types of glomerulonephritis.Pharmacologic inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) has been particularly well demonstrated to treat high BP and proteinuria successfully (1). Moreover, the decline of kidney function occurring in diabetic as well as in nondiabetic glomerulopathies was greatly reduced by these agents in many investigations (2,3). Although ARB have only recently been introduced to common clinical use, several studies reported equivalent renoprotection for both classes of agents, ACEI and ARB (1). However, the issue of long-term effects with regard to the kidney is not yet fully resolved, and the identification of patient groups in which one of these agents demonstrates potential advances over the other one remains of pivotal clinical interest.Angiotensin II plays a key role...

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“…From each pool one Northern blot analysis was performed for each parameter resulting in three Northern blots for every parameter analysed. RNA was extracted from the glomeruli using the acid guanidinium thiocyanate phenol chloroform extraction method [27] as we described previously [28]. Briefly, all probes were radiolabelled with [ 32 P]dCTP (Amersham) using the DECAprime DNA labelling kit (Ambion, Austin, Tex.…”

Section: Immunohistochemistrymentioning

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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Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat

Cited by 61 publications

References 36 publications

Murine models of polycystic kidney disease: molecular and therapeutic insights

Murine models of polycystic kidney disease: molecular and therapeutic insights

Angiotensin-Converting Enzyme Inhibition but not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis

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

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