Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis

Baricos, William H.; Cortez, Shirley L.; Lê, Quốc Chiểu; Wu, Li-Teh; Shaw, Elliott; Hanada, Kazunori; Shah, Sudhir V.

doi:10.1016/0003-9861(91)90222-5

Cited by 35 publications

(17 citation statements)

References 21 publications

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“…The functional significance of cathepsin L in podocyte pathobiology is underscored by the finding that cat L Ϫ/Ϫ podocytes are protected from cell detachment and cell-cell junction disassembly. These data also provide a molecular explanation for the previous observation that a specific cathepsin L inhibitor significantly reduces anti-GBM antibody-induced proteinuria (41).…”

Section: Down-regulation Of ␣ 3 Integrin Protects Against Pan-inducedsupporting

confidence: 67%

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Reiser¹,

Oh²,

Shirato³

et al. 2004

Journal of Biological Chemistry

163

135

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Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and ␣ 3 integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking ␣ 3 integrin. Similarly, acute functional inhibition of ␣ 3 integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Downregulation of ␣ 3 integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and ␣ 3 integrin.Glomerular podocytes serve as a final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes and the interposed slit diaphragm (SD) 1 All forms of nephrotic syndrome are characterized by podocyte foot process (FP) effacement and/or molecular reorganization of the slit diaphragm (1). FP effacement requires a precise interplay of multiple cellular functions including structural alterations of the cytoskeleton, movement of FP over the basement membrane, and reconstruction of the slit diaphragm (1). The discovery of several novel podocyte proteins and their mutation analysis including nephrin (2), CD2AP (3), ␣-actinin-4 (4), podocin (5), neph1 (6), and FAT (7) have shed light on the pathogenesis of FP effacement and proteinuria and emphasized the critical role of podocyte FP and the SD in maintaining the function of the glomerular filtration barrier.

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Section: Down-regulation Of ␣ 3 Integrin Protects Against Pan-inducedsupporting

confidence: 67%

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Reiser¹,

Oh²,

Shirato³

et al. 2004

Journal of Biological Chemistry

163

135

View full text Add to dashboard Cite

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“…PMN are thought to damage glomeruli, including in this disease, due to a combination of reactive oxygen species and proteolytic enzymes (7). Previous studies with this model in cathepsin G/elastase deficient-mice (23,24) and an injection of a cysteine proteinase inhibitor (25) demonstrated that only early proteinuria (within day 1) was dependent on proteinase, but PMN influx and development of glomerular injury were not. Thus, we postulated that the FcR-mediated PMN respiratory burst may be a rapid and powerful effector mechanism in the early cell recruitment.…”

Section: Mmune Complex (Ic)mentioning

confidence: 83%

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Suzuki

Gómez-Guerrero

Shirato³

et al. 2003

The Journal of Immunology

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In immune complex (IC) diseases, FcR are essential molecules facilitating polymorphonuclear cell (PMN) recruitment and effector functions at the IC site. Although FcR-dependent initial tethering and FcR/integrin-dependent PMN accumulation were postulated, their underlying mechanisms remain unclear. We here addressed potential mechanisms involved in PMN recruitment in acute IC glomerulonephritis (nephrotoxic nephritis). Since some renal cells may be recruited from bone marrow (BM) lineages, reconstitution studies with BM chimeras and PMN transfer between wild-type (WT) and FcR-deficient mice (γ−/−) were performed. Severe glomerular damage was induced in WT and Wγ chimeras (BM from WT to irradiated γ−/−), while it was absent in γ−/− and γW chimeras (γ−/− BM to WT). Moreover, WT PMN transfer, but not γ−/− PMN, reconstituted the disease in γ−/−, indicating that FcR on resident cells is not a prerequisite for PMN recruitment in this disease. Surprisingly, transferred WT PMN were recruited coincidentally with NF-κB activation and TNF-α overexpression even in glomeruli with preformed IC (nephrotoxic Ab administered 3 days previously), suggesting that PMN can initially be recruited via its own FcR without previous chemoattractant release. Furthermore, H2O2 inhibition by catalase attenuated the acute WT PMN recruitment and the induction of NF-κB and TNF-α much more than integrin (CD18) blockade, indicating a role for the respiratory burst before integrin-dependent accumulation. In coculture experiments with IC-stimulated PMN and glomeruli, PMN caused acute glomerular TNF-α expression predominantly via FcR-mediated H2O2 production. In conclusion, glomerular IC, even preformed, can cause PMN recruitment and injury through PMN FcR-mediated respiratory burst during initial PMN tethering to IC.

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“…There have been previous reports suggesting that protease inhibitors other than Ulinastatin may be effective in reducing proteinuria in rat anti-GBM nephritis [39, 40, 41]. In some of a these studies, however, inhibitors were given to rats for a short period, and their effects were evaluated only for the induction of proteinuria in the autologous phase [39, 40].…”

Section: Discussionmentioning

confidence: 99%

“…In some of a these studies, however, inhibitors were given to rats for a short period, and their effects were evaluated only for the induction of proteinuria in the autologous phase [39, 40]. Histological data were not presented.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Ulinastatin on Experimental Crescentic Glomerulonephritis in Rats

Koizumi

Kanai²,

Maezawa³

et al. 2000

Nephron

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Ulinastatin is a potent protease inhibitor purified from the human urine that has been used clinically to treat acute pancreatitis and circulatory shock. In the current study, we evaluated the therapeutic effects of Ulinastatin in a rat model of crescentic glomerulonephritis (CrGN) and investigated its putative mechanisms. Wistar-Kyoto rats were injected with nephrotoxic serum and received daily intraperitoneal injection of Ulinastatin. Ulinastatin treatment significantly reduced proteinuria and glomerular crescentic formation. Moreover, glomerular infiltration of neutrophils and ED1+ cells (monocytes/macrophages) was significantly suppressed by Ulinastatin. In contrast, the glomerular deposition of heterologous (rabbit) and autologous (rat) antibodies was not changed. Neither serum complement activation nor the anti-rabbit immune response was affected by Ulinastatin administration. Our results suggest that Ulinastatin has preventive effects on rat experimental CrGN, mediated at least in part by inhibiting intraglomerular infiltration of inflammatory cells.

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Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis

Cited by 35 publications

References 21 publications

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Therapeutic Effects of Ulinastatin on Experimental Crescentic Glomerulonephritis in Rats

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