Activities of cathepsins B and L in isolated nephron segments from proteinuric and nonproteinuric rats

Olbricht, C. J.; Cannon, J. K.; Garg, Lal C.; Tisher, C. Craig

doi:10.1152/ajprenal.1986.250.6.f1055

Cited by 38 publications

(41 citation statements)

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“…In addition, accumulating evidence suggests a strong link between heavy proteinuria, subsequent tubulointerstitial injury, and progressive kidney failure (23,24). Although several mechanisms are likely to contribute to this common pathway of progressive renal failure (25)(26)(27)(28)(29), mounting evidence indicates that intratubular complement activation, leading to tubular cell activation or injury and the release of proinflammatory cytokines, is the principal mediator of progressive tubulointerstitial damage (30 -33).…”

Section: The Role Of Proteinuria In Progressive Renal Disease: Evolvimentioning

confidence: 99%

Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

Hsu¹,

Couser²

2003

Journal of the American Society of Nephrology

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Abstract. The mechanisms by which increased urinary protein concentrations lead to nephrotoxic injury are certain to be multifactorial and involve complex interactions between numerous pathways of cellular damage mediated by both cellular and humoral pathways. These may include a major role for the podocyte in glomerular diseases leading to chronic renal failure, the loss of microvascular endothelium, the albumin-induced upregulation of renal cytokines and growth factors that promote tubulointerstitial injury by inflammation and fibrogenesis, and the role of complement-mediated tubulointerstitial injury due to proteinuria. This review will focus on the last mechanism, and emphasize recent studies implicating a primary role for activation of complement in proteinuric urine as the principal mediator of tubulointerstitial damage and progressive renal disease in various experimental animal models of nephrosis. It will be our contention that intraluminal activation of the terminal complement cascade leading to the formation of the C5b-9 membrane attack complex is the principal mediator of chronic progressive interstitial damage and progressive renal failure irrespective of the type of primary glomerular injury. This paradigm has important implications for the potential therapeutic role of complement inhibitors that are currently being developed.

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Section: The Role Of Proteinuria In Progressive Renal Disease: Evolvimentioning

confidence: 99%

Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

Hsu¹,

Couser²

2003

Journal of the American Society of Nephrology

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“…Both genes have been implicated previously in the development of proteinuria and renal organ damage. 30,31,36,37 Sod3 encodes a member of the superoxide dismutase family. Superoxide dismutases are antioxidant enzymes that catalyze the dismutation of 2 superoxide radicals into hydrogen peroxide and oxygen and thereby protect tissue from oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…42 CTSL activity in the proximal tubule increases in proteinuric rats, possibly in response to the increased load of filtered protein. 30,31 CTSL is also expressed in a cytosolic form in glomerular podocytes, where it is directly involved in destabilization of the filtration barrier. In Ctsl-deficient mice, proteinuria and foot process effacement, that is, alteration of the podocyte filtration barrier, are abolished.…”

Section: Discussionmentioning

confidence: 99%

“…We selected Ctsl for further biomarker investigation, because the encoded protein has been shown to play a role in renal damage. 30,31 Immunoassays Urine samples were collected weekly in separate groups of dTGR males and females and their respective SD controls, starting at 3 weeks of age, until week 7. The urinary protein levels of CTSL and KIM-1 were overall lower in SD rats compared with dTGRs ( Figure 2).…”

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confidence: 99%

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Identification of Cathepsin L as a Potential Sex-Specific Biomarker for Renal Damage

et al. 2011

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Abstract-The renin-angiotensin system is a well-known regulator of blood pressure and plays an important role in the pathogenesis of cardiovascular disease and renal damage. Genetic factors, including single nucleotide polymorphisms and sex, are increasingly recognized as potential risk factors for the development of cardiovascular disease. Double transgenic rats (dTGRs), harboring human renin and angiotensinogen genes, were used in this study to investigate potential sex differences influencing renal function and renal gene expression. dTGR males and females had comparable increases in blood pressure, whereas body weight, albuminuria/proteinuria, and urine flow rate were higher in males. At 8 weeks of age, renal plasma flow and glomerular filtration rate were proportionally lower in males, and renal vascular resistance tended to be higher. Males developed more severe tubulointerstitial and vascular lesions. By the end of week 8, 40% of the males but none of the females had died. Genome expression studies were performed with RNA from kidneys of 7-week-old male and female dTGRs and control rats to further investigate the sex-related differences on a molecular level. Forty-five genes showed sex-dependent expression patterns in dTGRs that were significantly different compared to controls. Cathepsin L, one of the genes differentially expressed between the sexes, was also shown to be strongly associated with the degree of renal injury. In dTGRs, urinary cathepsin L at week 7 was higher in males (nanograms per 24 hours: male, 512Ϯ163; female, 132Ϯ70). These results reveal a potential new biomarker for the personalized diagnosis and management of chronic kidney disease. Key Words: sex difference Ⅲ renin-angiotensin system Ⅲ double transgenic rats Ⅲ hypertension Ⅲ renal disease Ⅲ oxidative stress Ⅲ gene expression I n developed countries, the life expectancy of men is usually shorter than that of women. 1 Men tend to have higher blood pressure than do premenopausal women of similar age, 2,3 and this difference is associated with a greater risk for the development of cardiovascular disease and renal damage. End-stage renal disease is indeed more frequent in men than in women, 4 and the rate of progression of chronic renal disease is generally more rapid in men. 5,6 There is ample evidence to suggest an involvement of the renin-angiotensin system (RAS) in blood pressure increase and kidney failure. 7,8 An impact of sex has also been reported in experimental animal models of renal disease and hypertension, including a rat model of mild chronic inhibition of NO synthesis, 9 spontaneously hypertensive rats, 10 deoxycorticosterone acetate-salt rats, 11 Dahl salt-sensitive rats, 12 and the Goldblatt 2-kidney, 1-clip rats. 13 Because, in these models, the sexrelated differences in the development of hypertension and renal damage were associated with the RAS, the double transgenic rat (dTGR), expressing both human renin and angiotensinogen genes, provides an ideal model to explore sex-dependent responses to RAS dysregulation.S...

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“…Assay of Cathepsin L Activity-Cathepsin L activity in cytoplasmic extracts from monolayer or spheroid cultured hepatocytes was assessed by the Inubushi method (29) using a substrate for both cathepsin B and cathepsin L (Z-Phe-Arg-4-methylcoumaryl-7-amide (MCA), Peptide Institute, Osaka, Japan) (30) in the presence of specific cathepsin B inhibitor, CA-074 (25,26). Ten micromoles of the substrate was incubated with the cytoplasmic extract from monolayers or spheroids in the cathepsin assay buffer (100 mM sodium acetate, pH 5.5, 8 mM L-cysteine, 1 mM EDTA) in the presence of 10 Ϫ4 M of CA-074 at 37°C for 6 min.…”

Section: Immunoprecipitation Of In Vitro Translated Rxr␣ After Proteomentioning

confidence: 99%

Intracellular Proteolytic Cleavage of 9-cis-Retinoic Acid Receptor α by Cathepsin L-type Protease Is a Potential Mechanism for Modulating Thyroid Hormone Action

Nagaya

Murata

Yamaguchi

et al. 1998

Journal of Biological Chemistry

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We previously reported that the responsiveness of hepatocytes to thyroid hormone is markedly attenuated when they were cultured as monolayers rather than spheroids. To elucidate the mechanisms underlying the altered responsiveness, thyroid hormone receptor auxiliary proteins in the hepatocytes were analyzed by electrophoretic mobility shift assay. The major thyroid hormone receptor auxiliary protein was identified as 9-cisretinoic acid receptor ␣ (RXR␣) in the hepatocytes regardless of the culture conditions. The cytoplasmic fraction was shown to contain a protease(s) that cleaves RXR␣ at its amino terminus. The presence of the protease in the cytosol, but not in the nucleus, was ascertained by incubating full-length 35 S-labeled RXR␣ with each fraction. Using various protease inhibitors, it was shown that cathepsin L-type protease could participate in the cleavage of the RXR␣. The enzyme activity was much higher in the monolayers than the spheroids. Inhibition of this enzyme activity in the monolayer hepatocyte resulted in the increase of nuclear RXR␣ protein and the augmentation of T 3 -dependent induction of spot 14 mRNA. These results suggest that the changes in cathepsin L-type protease activity in the cytosol may alter the turnover of RXR␣ in the nucleus and modify the function of steroid receptor superfamilies that heterodimerize with RXR␣.Thyroid hormones are essential for normal growth and development as well as for the regulation of a variety of metabolic pathways (1). These effects are mediated by thyroid hormone receptors (TRs), 1 which activate or repress the transcription of specific target genes in a ligand-dependent manner (2). TRs belong to members of the family of nuclear receptors which also include several steroid, retinoic acid, and vitamin D 3 receptors. TRs are encoded by two genes, TR␣ and TR␤, as well as alternative splicing products of each (3). For transcriptional regulation by thyroid hormones, TRs bind to a specific DNA sequence (thyroid-hormone responsive element, TRE) of target genes by forming a monomer, a homodimer, and a heterodimer with TR auxiliary proteins (TRAPs) (4). TREs are composed of the arrangement of two common hexameric DNA half-site sequences (AGGTCA). The orientation of two half-sites is headto-head (palindrome, Pal) or in an opposite orientation as an inverted palindrome (Lap), with the half-sites arranged headto-tail as a direct repeat with 4 spacing (DR4). The heterodimer formation (TR/TRAP) on these TREs is suggested to be more stable and important for transcriptional regulation (5). Several studies (6 -8) identified 9-cis-retinoic acid receptors (RXRs), which are also members of the nuclear receptor superfamily, as TRAPs in most tissues. Also demonstrated was that preferential expression of RXR isoforms in certain cell lines or tissues results in the apparent heterogeneity of TRAP on EMSA (9).One of the major target organs for thyroid hormones is the liver, in which a number of genes in the metabolic pathways such as spot 14 (10), malic enzyme (11), and type I...

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Activities of cathepsins B and L in isolated nephron segments from proteinuric and nonproteinuric rats

Cited by 38 publications

References 0 publications

Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

Identification of Cathepsin L as a Potential Sex-Specific Biomarker for Renal Damage

Intracellular Proteolytic Cleavage of 9-cis-Retinoic Acid Receptor α by Cathepsin L-type Protease Is a Potential Mechanism for Modulating Thyroid Hormone Action

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