Research ExplorerPublicationsCathepsin S Cleavage of Protease-Activated Receptor-2 on End...

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Standard

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications. / Kumar Vr, Santhosh; Darisipudi, Murthy N; Steiger, Stefanie; Devarapu, Satish Kumar; Tato, Maia; Kukarni, Onkar P; Mulay, Shrikant R; Thomasova, Dana; Popper, Bastian; Demleitner, Jana; Zuchtriegel, Gabriele; Reichel, Christoph; Cohen, Clemens D; Lindenmeyer, Maja T; Liapis, Helen; Moll, Solange; Reid, Emma; Stitt, Alan W; Schott, Brigitte; Gruner, Sabine; Haap, Wolfgang; Ebeling, Martin; Hartmann, Guido; Anders, Hans-Joachim.

In: J AM SOC NEPHROL, Vol. 27, No. 6, 06.2016, p. 1635-49.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Kumar Vr, S, Darisipudi, MN, Steiger, S, Devarapu, SK, Tato, M, Kukarni, OP, Mulay, SR, Thomasova, D, Popper, B, Demleitner, J, Zuchtriegel, G, Reichel, C, Cohen, CD, Lindenmeyer, MT, Liapis, H, Moll, S, Reid, E, Stitt, AW, Schott, B, Gruner, S, Haap, W, Ebeling, M, Hartmann, G & Anders, H-J 2016, 'Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications', J AM SOC NEPHROL, vol. 27, no. 6, pp. 1635-49. https://doi.org/10.1681/ASN.2015020208

APA

Kumar Vr, S., Darisipudi, M. N., Steiger, S., Devarapu, S. K., Tato, M., Kukarni, O. P., Mulay, S. R., Thomasova, D., Popper, B., Demleitner, J., Zuchtriegel, G., Reichel, C., Cohen, C. D., Lindenmeyer, M. T., Liapis, H., Moll, S., Reid, E., Stitt, A. W., Schott, B., ... Anders, H-J. (2016). Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications. J AM SOC NEPHROL, 27(6), 1635-49. https://doi.org/10.1681/ASN.2015020208

Vancouver

Kumar Vr S, Darisipudi MN, Steiger S, Devarapu SK, Tato M, Kukarni OP et al. Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications. J AM SOC NEPHROL. 2016 Jun;27(6):1635-49. https://doi.org/10.1681/ASN.2015020208

Bibtex

@article{bbf049fffff846e6aada114dc5f68fd0,
title = "Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications",
abstract = "Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.",
keywords = "Animals, Cathepsins, Cells, Cultured, Diabetic Angiopathies, Endothelial Cells, Kidney Glomerulus, Male, Mice, Microvessels, Proline, Receptor, PAR-2, Urothelium, Journal Article, Research Support, Non-U.S. Gov't",
author = "{Kumar Vr}, Santhosh and Darisipudi, {Murthy N} and Stefanie Steiger and Devarapu, {Satish Kumar} and Maia Tato and Kukarni, {Onkar P} and Mulay, {Shrikant R} and Dana Thomasova and Bastian Popper and Jana Demleitner and Gabriele Zuchtriegel and Christoph Reichel and Cohen, {Clemens D} and Lindenmeyer, {Maja T} and Helen Liapis and Solange Moll and Emma Reid and Stitt, {Alan W} and Brigitte Schott and Sabine Gruner and Wolfgang Haap and Martin Ebeling and Guido Hartmann and Hans-Joachim Anders",
note = "Copyright {\textcopyright} 2016 by the American Society of Nephrology.",
year = "2016",
month = jun,
doi = "10.1681/ASN.2015020208",
language = "English",
volume = "27",
pages = "1635--49",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "6",

}

RIS

TY - JOUR

T1 - Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

AU - Kumar Vr, Santhosh

AU - Darisipudi, Murthy N

AU - Steiger, Stefanie

AU - Devarapu, Satish Kumar

AU - Tato, Maia

AU - Kukarni, Onkar P

AU - Mulay, Shrikant R

AU - Thomasova, Dana

AU - Popper, Bastian

AU - Demleitner, Jana

AU - Zuchtriegel, Gabriele

AU - Reichel, Christoph

AU - Cohen, Clemens D

AU - Lindenmeyer, Maja T

AU - Liapis, Helen

AU - Moll, Solange

AU - Reid, Emma

AU - Stitt, Alan W

AU - Schott, Brigitte

AU - Gruner, Sabine

AU - Haap, Wolfgang

AU - Ebeling, Martin

AU - Hartmann, Guido

AU - Anders, Hans-Joachim

N1 - Copyright © 2016 by the American Society of Nephrology.

PY - 2016/6

Y1 - 2016/6

N2 - Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.

AB - Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.

KW - Animals

KW - Cathepsins

KW - Cells, Cultured

KW - Diabetic Angiopathies

KW - Endothelial Cells

KW - Kidney Glomerulus

KW - Male

KW - Mice

KW - Microvessels

KW - Proline

KW - Receptor, PAR-2

KW - Urothelium

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1681/ASN.2015020208

DO - 10.1681/ASN.2015020208

M3 - SCORING: Journal article

C2 - 26567242

VL - 27

SP - 1635

EP - 1649

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 6

ER -