- Email: [email protected]
Cathepsins are potential therapeutic targets in kidney disease
commentary
3.
4.
5.
6.
glomerulopathy and proximal tubular injury. Kidney Int. 2016;90:997–1011. Herman-Edelstein M, Scherzer P, Tobar A, et al. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. 2014;55:561–572. Kume S, Uzu T, Araki S, et al. Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol. 2007;18:2715–2723. Kang HM, Ahn SH, Choi P, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21:37–46. Munusamy S, do Carmo JM, Hosler JP, et al. Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in
the presence or absence of leptin. Am J Physiol Renal Physiol. 2015;309:F731–F743. 7. Hardie DG. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol. 2015;33:1–7. 8. Birk AV, Chao WM, Bracken C, et al. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171: 2017–2028. 9. Anderson EJ, Lustig ME, Boyle KE, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–581.
Cathepsins are potential therapeutic targets in kidney disease Santhosh Kumar VR1 and Hans-Joachim Anders1 Cathepsins are a class of proteases with diverse biological activities inside and, in part, also outside cells. Recent studies suggest that cathepsins are involved in the pathogenesis of diabetic nephropathy and in disease activity of autoimmune immune complex glomerulonephritis. Targeting specific cathepsins with suitable antagonists may hold promises for therapeutic interventions. Kidney International (2016) 90, 933–935; http://dx.doi.org/10.1016/j.kint.2016.07.034 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see basic research on page 1012
I
n this issue of Kidney International, Garsen et al.1 (2016) report cathepsin L to be crucial for the development of early experimental diabetic nephropathy. Cathepsin L is a lysosomal cysteine protease that degrades numerous proteins including components of the glomerular filtration barrier such as CD2-associated protein, synaptopodin, and dynamin.2 In addition, cathepsin L can activate proteins that are involved in the pathogenesis of diabetic nephropathy such as heparan 1 Medizinische Klinik and Poliklinik IV, Klinikum der Ludwig Maximilians Universität München, Munich, Germany
Correspondence: Hans-Joachim Anders, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München – Innenstadt, Ziemssenstr. 1, 80336 München, Germany. E-mail: hjanders@ med.uni-muenchen.de Kidney International (2016) 90, 928–942
sulfate endoglycosidase (Figure 1). Cathepsin L–deficient mice displayed identical hyperglycemia upon inducing type 1 diabetes with the beta cell toxin streptozotocin but were protected from albuminuria, mesangial sclerosis, and tubulointerstitial fibrosis, implying a specific role for cathepsin L in glomerular injury. Indeed, these findings were associated with preserved immunostaining for synaptopodin and podocyte foot process ultrastructure in transmission electron microscopy. In addition, cathepsin L deficiency abrogated heparan sulfate endoglycosidase and preserved glomerular heparan sulfate expression, potentially at the luminal aspect of glomerular endothelial cells. These data are potentially important because endothelial cell and podocyte ultrastructure,
two important components of the glomerular filtration barrier, are the first interface injured in diabetes.3 Particularly, endothelial cells are affected by early diabetes, a process referred to as “endothelial dysfunction.”3 Endothelial dysfunction presents as a state of increased activation, which implies induction of cytokines, chemokines, and adhesion molecules, cell stress, and impaired vascular barrier function.3 The latter manifests as fluid and protein leakage into perivascular compartments, a process that remains invisible in most organs except for the kidney (microalbuminuria) and the retina (cotton wool spots; Figure 1).3 Endothelial dysfunction is both a cause and consequence of breaking down the endothelial glycocalix along the luminal plasma membrane.3 The glycocalix is a hydrogel that buries all endothelial cell surface receptors and, hence, attenuates ligand-receptor interactions, for example, immune cells from binding to adhesion molecules. Enzymes that break down the glycocalix induce a “low tide-like” thinning of this gel, which promotes not only the passage of plasma proteins like albumin, but also facilitates interactions of endothelial surface cell molecules with soluble or cell bound ligands, i.e., Toll-like receptor agonist/receptor, chemokine/chemokine receptor, or adhesion molecule/leukocyte integrin interactions. The result is inflammation, leukocyte recruitment, and, in the glomerulus, albuminuria.3 Cathepsin L may be an upstream regulator of glycocalix breakdown in addition to its well-established role on podocyte barrier proteins (Figure 1).2 Since insulin and antidiabetic drugs have become available, the most prevalent clinical presentation of diabetes has shifted from diabetic coma to macroand microvascular diabetes complications. “Diabetic nephropathy” was initially defined in patients with type 1 diabetes that presents at a young age without concomitant (kidney) diseases. In contrast, patients with type 2 diabetes often show concomitant nondiabetic kidney disease and/or aging-related nephron loss. It is of note that research shows that streptozotocin-induced type 1 diabetes in young and healthy rodents 933
commentary
Figure 1 | Pathogenic effects of cysteine proteases cathepsin L and cathepsin S. In antigen-presenting cells cathepsin S is involved in the enzymatic cleavage of the invariant chain during processing of immature major histocompatibility complex II (a). Only mature major histocompatibility complex II is ready to pick up antigenic peptide and present it to lymphocytes. The left part of the glomeruli shows healthy endothelial capillary with intact slit membrane and heparan sulfate expression (in glow) (b). Healthy podocytes show intact actin-associated synaptopodin with secondary foot processes and membrane heparan sulfate (in glow). Right part displays cathepsin L reducing membrane heparan sulfate on endothelial cells and regulating structural podocyte protein expression promoting foot process effacement and albuminuria. In addition, cathepsin S released by activated immune cells activates protease-activated receptor 2 on the endothelial cell surface causing endothelial dysfunction, a process promoting plasma leakage and albuminuria as well. The latter mechanism also contributes to endothelial dysfunction in the retina, implying plasma leakage in the retina, presenting as cotton wool spots (c). Cat, cathepsin; CLIP, class II-associated invariant chain peptide; ER, endoplasmic reticulum; MHC-II, major histocompatibility complex II; PAR-2, protease-activated receptor 2.
mimics type 1 but not necessarily type 2 “diabetic nephropathy,” the latter being by far the most prevalent form of diabetes on a global scale. Hence, wide generalization of such data on “diabetic nephropathy” should be avoided. Garsen et al. admit that their studies can only allow conclusions on early (type 1) diabetic nephropathy, which is somewhat in conflict with the reported elevations of blood urea nitrogen and plasma creatinine that come without any relevant 934
glomerulosclerosis or obvious nephron loss.1 For the sake of translational relevance it would be valuable to complement such data sets with experiments using models of type 2 diabetes with considerable concomitant nephron loss. If the proposed molecular mechanisms are valid, also a more advanced type 2 “diabetic nephropathy” should benefit from cathepsin L deficiency. Such data were recently reported on another cathepsin, i.e., cathepsin S. Kumar
et al. used uninephrectomy in db/db mice to mimic an advanced stage of type 2 diabetic nephropathy before onset of feeding a specific cathepsin S antagonist or vehicle.4 Cathepsin S blockade markedly attenuated diabetic retinopathy and glomerulosclerosis, i.e., albuminuria, podocyte loss, and glomerulosclerosis (Figure 1). The protective effect on glomerular endothelial cells was particularly striking and consistent with other in vivo and in vitro models of cathepsin S–induced endothelial injury. Kidney International (2016) 90, 928–942
commentary
Cathepsin S was found to specifically activate protease-activated receptor (PAR)-2 on endothelial cells by hydrolyzing the extracellular N terminus of human PAR2 at the E(56)YT(57) site, which is 20 residues downstream of the canonical trypsin cleavage site R36YS37.5 This is possible because, unlike other cathepsins, which are mainly localized and biologically active at low pH inside intracellular lysosomes, cathepsin S is also biologically activated at a physiological pH outside cells. Cathepsin S is secreted by activated monocytes, neutrophils, and endothelial cells and facilitates endothelial dysfunction in many systemic disorders including atherosclerosis.6 Indeed, epidemiological studies revealed strong associations of circulating cathepsin S levels with cardiovascular morbidity and mortality in older patients with hypertension and other chronic morbidities.7 However, like cathepsin L, cathepsin S also has proteolytic functions inside endosomal compartments. One substrate of cathepsin S has raised particular attention, i.e., the invariant chain. The invariant chain is a protein that covers the peptide-binding domain of the major histocompatibility complex (MHC) II (Figure 1).8 MHC-II is a nonredundant element of antigenpresentation machinery that assures adaptive immunity to extracellular antigens by presenting antigenic epitopes fixed to MHC-II’s binding domain to the T cell repertoire.8 Peptide loading is a highly regulated process at the final stage of MHC-II maturation in the endoplasmic reticulum. The invariant chain assures that no other protein attaches to the binding domain before the peptide loading step.8 Removing the invariant chain involves a stepwise proteolytic shortening by various enzymes, of which cathepsin S in an important one (Figure 1). Genetic deletion or pharmaceutical inhibition of cathepsin S makes it impossible to load MHC-II with antigenic peptide, an effect that abrogates the presentation of
Kidney International (2016) 90, 928–942
extracellular antigens. This implies that cathepsin S inhibitors not only elicit protective effects on vascular structures but are highly selective but potent immunosuppressive drugs at first. Indeed, cathepsin S inhibition has profound effects on a larger number of models of autoimmune disease including lupus-like immune complex glomerulonephritis.9 Conceptually, the dual effect of blocking MHC-II–mediated antigen presentation and PAR-2– mediated vascular injury renders cathepsin S inhibitors as particularly attractive for the treatment of autoimmune diseases with vascular complications such as autoimmune vasculitis and lupus erythematosus with their renal complications. In addition, this dual effect should be particularly potent in alloimmune tissue injuries such as acute rejection or chronic allograft dysfunction, but experimental data on this aspect are not yet available. How about diabetes? The immunosuppressive effects of cathepsin S inhibitors preclude their use in patients with diabetes, a concern that could be simply circumvented by using PAR-2 inhibitors that can abrogate cathepsin S–mediated vascular complications in diabetes without interfering with antigen presentation.4 The elegant study by Garsen et al. focuses on early changes in a mouse model of type 1 diabetes.1 However, the concept raised here raises hope for cathepsin L inhibitors to be potentially useful also in human diabetic kidney disease. However, in light of the numerous substrates of cathepsin, wide generalizations from such data are potentially misleading. As demonstrated for cathepsin S inhibition, other substrates may lead to unexpected effects of such drugs, which may be additive, as pointed out for autoimmune diseases, but could be potentially dangerous as pointed out for diabetes. This implies that unspecific cathepsin inhibitors will hold the greatest risk for unwanted side effects, and even
highly specific cathepsin L inhibitors may still have numerous unexpected effects because of the substrate promiscuity of the cathepsins, a phenomenon to be carefully explored before human trials should be performed. However, the study by Garsen et al. is an important piece of evidence on the diverse roles of cysteine proteases in kidney disease. DISCLOSURE
All the authors declared no competing interests. ACKNOWLEDGMENT
HJA was supported by European Union’s Horizon 2020 research and innovation program under grant no. 668036 (project RELENT). The views expressed here are the responsibility of the author only. The EU Commission takes no responsibility for any use made of the information set out. REFERENCES 1. Garsen M, Rops ALWMM, Dijkman H, et al. Cathepsin L is crucial for the development of early experimental diabetic nephropathy. Kidney Int. 2016;90:1012–1022. 2. Sever S, Reiser J. CD2AP, dendrin, and cathepsin L in the kidney. Am J Pathol. 2015;185:3129–3130. 3. Advani A, Gilbert RE. The endothelium in diabetic nephropathy. Semin Nephrol. 2012;32:199–207. 4. Kumar Vr S, Darisipudi MN, Steiger S, et al. Cathepsin S cleavage of protease-activated receptor-2 on endothelial cells promotes microvascular diabetes complications. J Am Soc Nephrol. 2016;27:1635–1649. 5. Zhao P, Lieu T, Barlow N, et al. Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. J Biol Chem. 2014;289: 27215–27234. 6. Sukhova GK, Zhang Y, Pan JH, et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;111:897–906. 7. Jobs E, Ingelsson E, Riserus U, et al. Association between serum cathepsin S and mortality in older adults. JAMA. 2011;306:1113–1121. 8. Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15: 203–216. 9. Rupanagudi KV, Kulkarni OP, Lichtnekert J, et al. Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming. Ann Rheum Dis. 2015;74: 452–463.
935
3.
4.
5.
6.
glomerulopathy and proximal tubular injury. Kidney Int. 2016;90:997–1011. Herman-Edelstein M, Scherzer P, Tobar A, et al. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. 2014;55:561–572. Kume S, Uzu T, Araki S, et al. Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol. 2007;18:2715–2723. Kang HM, Ahn SH, Choi P, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21:37–46. Munusamy S, do Carmo JM, Hosler JP, et al. Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in
the presence or absence of leptin. Am J Physiol Renal Physiol. 2015;309:F731–F743. 7. Hardie DG. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol. 2015;33:1–7. 8. Birk AV, Chao WM, Bracken C, et al. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171: 2017–2028. 9. Anderson EJ, Lustig ME, Boyle KE, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–581.
Cathepsins are potential therapeutic targets in kidney disease Santhosh Kumar VR1 and Hans-Joachim Anders1 Cathepsins are a class of proteases with diverse biological activities inside and, in part, also outside cells. Recent studies suggest that cathepsins are involved in the pathogenesis of diabetic nephropathy and in disease activity of autoimmune immune complex glomerulonephritis. Targeting specific cathepsins with suitable antagonists may hold promises for therapeutic interventions. Kidney International (2016) 90, 933–935; http://dx.doi.org/10.1016/j.kint.2016.07.034 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see basic research on page 1012
I
n this issue of Kidney International, Garsen et al.1 (2016) report cathepsin L to be crucial for the development of early experimental diabetic nephropathy. Cathepsin L is a lysosomal cysteine protease that degrades numerous proteins including components of the glomerular filtration barrier such as CD2-associated protein, synaptopodin, and dynamin.2 In addition, cathepsin L can activate proteins that are involved in the pathogenesis of diabetic nephropathy such as heparan 1 Medizinische Klinik and Poliklinik IV, Klinikum der Ludwig Maximilians Universität München, Munich, Germany
Correspondence: Hans-Joachim Anders, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München – Innenstadt, Ziemssenstr. 1, 80336 München, Germany. E-mail: hjanders@ med.uni-muenchen.de Kidney International (2016) 90, 928–942
sulfate endoglycosidase (Figure 1). Cathepsin L–deficient mice displayed identical hyperglycemia upon inducing type 1 diabetes with the beta cell toxin streptozotocin but were protected from albuminuria, mesangial sclerosis, and tubulointerstitial fibrosis, implying a specific role for cathepsin L in glomerular injury. Indeed, these findings were associated with preserved immunostaining for synaptopodin and podocyte foot process ultrastructure in transmission electron microscopy. In addition, cathepsin L deficiency abrogated heparan sulfate endoglycosidase and preserved glomerular heparan sulfate expression, potentially at the luminal aspect of glomerular endothelial cells. These data are potentially important because endothelial cell and podocyte ultrastructure,
two important components of the glomerular filtration barrier, are the first interface injured in diabetes.3 Particularly, endothelial cells are affected by early diabetes, a process referred to as “endothelial dysfunction.”3 Endothelial dysfunction presents as a state of increased activation, which implies induction of cytokines, chemokines, and adhesion molecules, cell stress, and impaired vascular barrier function.3 The latter manifests as fluid and protein leakage into perivascular compartments, a process that remains invisible in most organs except for the kidney (microalbuminuria) and the retina (cotton wool spots; Figure 1).3 Endothelial dysfunction is both a cause and consequence of breaking down the endothelial glycocalix along the luminal plasma membrane.3 The glycocalix is a hydrogel that buries all endothelial cell surface receptors and, hence, attenuates ligand-receptor interactions, for example, immune cells from binding to adhesion molecules. Enzymes that break down the glycocalix induce a “low tide-like” thinning of this gel, which promotes not only the passage of plasma proteins like albumin, but also facilitates interactions of endothelial surface cell molecules with soluble or cell bound ligands, i.e., Toll-like receptor agonist/receptor, chemokine/chemokine receptor, or adhesion molecule/leukocyte integrin interactions. The result is inflammation, leukocyte recruitment, and, in the glomerulus, albuminuria.3 Cathepsin L may be an upstream regulator of glycocalix breakdown in addition to its well-established role on podocyte barrier proteins (Figure 1).2 Since insulin and antidiabetic drugs have become available, the most prevalent clinical presentation of diabetes has shifted from diabetic coma to macroand microvascular diabetes complications. “Diabetic nephropathy” was initially defined in patients with type 1 diabetes that presents at a young age without concomitant (kidney) diseases. In contrast, patients with type 2 diabetes often show concomitant nondiabetic kidney disease and/or aging-related nephron loss. It is of note that research shows that streptozotocin-induced type 1 diabetes in young and healthy rodents 933
commentary
Figure 1 | Pathogenic effects of cysteine proteases cathepsin L and cathepsin S. In antigen-presenting cells cathepsin S is involved in the enzymatic cleavage of the invariant chain during processing of immature major histocompatibility complex II (a). Only mature major histocompatibility complex II is ready to pick up antigenic peptide and present it to lymphocytes. The left part of the glomeruli shows healthy endothelial capillary with intact slit membrane and heparan sulfate expression (in glow) (b). Healthy podocytes show intact actin-associated synaptopodin with secondary foot processes and membrane heparan sulfate (in glow). Right part displays cathepsin L reducing membrane heparan sulfate on endothelial cells and regulating structural podocyte protein expression promoting foot process effacement and albuminuria. In addition, cathepsin S released by activated immune cells activates protease-activated receptor 2 on the endothelial cell surface causing endothelial dysfunction, a process promoting plasma leakage and albuminuria as well. The latter mechanism also contributes to endothelial dysfunction in the retina, implying plasma leakage in the retina, presenting as cotton wool spots (c). Cat, cathepsin; CLIP, class II-associated invariant chain peptide; ER, endoplasmic reticulum; MHC-II, major histocompatibility complex II; PAR-2, protease-activated receptor 2.
mimics type 1 but not necessarily type 2 “diabetic nephropathy,” the latter being by far the most prevalent form of diabetes on a global scale. Hence, wide generalization of such data on “diabetic nephropathy” should be avoided. Garsen et al. admit that their studies can only allow conclusions on early (type 1) diabetic nephropathy, which is somewhat in conflict with the reported elevations of blood urea nitrogen and plasma creatinine that come without any relevant 934
glomerulosclerosis or obvious nephron loss.1 For the sake of translational relevance it would be valuable to complement such data sets with experiments using models of type 2 diabetes with considerable concomitant nephron loss. If the proposed molecular mechanisms are valid, also a more advanced type 2 “diabetic nephropathy” should benefit from cathepsin L deficiency. Such data were recently reported on another cathepsin, i.e., cathepsin S. Kumar
et al. used uninephrectomy in db/db mice to mimic an advanced stage of type 2 diabetic nephropathy before onset of feeding a specific cathepsin S antagonist or vehicle.4 Cathepsin S blockade markedly attenuated diabetic retinopathy and glomerulosclerosis, i.e., albuminuria, podocyte loss, and glomerulosclerosis (Figure 1). The protective effect on glomerular endothelial cells was particularly striking and consistent with other in vivo and in vitro models of cathepsin S–induced endothelial injury. Kidney International (2016) 90, 928–942
commentary
Cathepsin S was found to specifically activate protease-activated receptor (PAR)-2 on endothelial cells by hydrolyzing the extracellular N terminus of human PAR2 at the E(56)YT(57) site, which is 20 residues downstream of the canonical trypsin cleavage site R36YS37.5 This is possible because, unlike other cathepsins, which are mainly localized and biologically active at low pH inside intracellular lysosomes, cathepsin S is also biologically activated at a physiological pH outside cells. Cathepsin S is secreted by activated monocytes, neutrophils, and endothelial cells and facilitates endothelial dysfunction in many systemic disorders including atherosclerosis.6 Indeed, epidemiological studies revealed strong associations of circulating cathepsin S levels with cardiovascular morbidity and mortality in older patients with hypertension and other chronic morbidities.7 However, like cathepsin L, cathepsin S also has proteolytic functions inside endosomal compartments. One substrate of cathepsin S has raised particular attention, i.e., the invariant chain. The invariant chain is a protein that covers the peptide-binding domain of the major histocompatibility complex (MHC) II (Figure 1).8 MHC-II is a nonredundant element of antigenpresentation machinery that assures adaptive immunity to extracellular antigens by presenting antigenic epitopes fixed to MHC-II’s binding domain to the T cell repertoire.8 Peptide loading is a highly regulated process at the final stage of MHC-II maturation in the endoplasmic reticulum. The invariant chain assures that no other protein attaches to the binding domain before the peptide loading step.8 Removing the invariant chain involves a stepwise proteolytic shortening by various enzymes, of which cathepsin S in an important one (Figure 1). Genetic deletion or pharmaceutical inhibition of cathepsin S makes it impossible to load MHC-II with antigenic peptide, an effect that abrogates the presentation of
Kidney International (2016) 90, 928–942
extracellular antigens. This implies that cathepsin S inhibitors not only elicit protective effects on vascular structures but are highly selective but potent immunosuppressive drugs at first. Indeed, cathepsin S inhibition has profound effects on a larger number of models of autoimmune disease including lupus-like immune complex glomerulonephritis.9 Conceptually, the dual effect of blocking MHC-II–mediated antigen presentation and PAR-2– mediated vascular injury renders cathepsin S inhibitors as particularly attractive for the treatment of autoimmune diseases with vascular complications such as autoimmune vasculitis and lupus erythematosus with their renal complications. In addition, this dual effect should be particularly potent in alloimmune tissue injuries such as acute rejection or chronic allograft dysfunction, but experimental data on this aspect are not yet available. How about diabetes? The immunosuppressive effects of cathepsin S inhibitors preclude their use in patients with diabetes, a concern that could be simply circumvented by using PAR-2 inhibitors that can abrogate cathepsin S–mediated vascular complications in diabetes without interfering with antigen presentation.4 The elegant study by Garsen et al. focuses on early changes in a mouse model of type 1 diabetes.1 However, the concept raised here raises hope for cathepsin L inhibitors to be potentially useful also in human diabetic kidney disease. However, in light of the numerous substrates of cathepsin, wide generalizations from such data are potentially misleading. As demonstrated for cathepsin S inhibition, other substrates may lead to unexpected effects of such drugs, which may be additive, as pointed out for autoimmune diseases, but could be potentially dangerous as pointed out for diabetes. This implies that unspecific cathepsin inhibitors will hold the greatest risk for unwanted side effects, and even
highly specific cathepsin L inhibitors may still have numerous unexpected effects because of the substrate promiscuity of the cathepsins, a phenomenon to be carefully explored before human trials should be performed. However, the study by Garsen et al. is an important piece of evidence on the diverse roles of cysteine proteases in kidney disease. DISCLOSURE
All the authors declared no competing interests. ACKNOWLEDGMENT
HJA was supported by European Union’s Horizon 2020 research and innovation program under grant no. 668036 (project RELENT). The views expressed here are the responsibility of the author only. The EU Commission takes no responsibility for any use made of the information set out. REFERENCES 1. Garsen M, Rops ALWMM, Dijkman H, et al. Cathepsin L is crucial for the development of early experimental diabetic nephropathy. Kidney Int. 2016;90:1012–1022. 2. Sever S, Reiser J. CD2AP, dendrin, and cathepsin L in the kidney. Am J Pathol. 2015;185:3129–3130. 3. Advani A, Gilbert RE. The endothelium in diabetic nephropathy. Semin Nephrol. 2012;32:199–207. 4. Kumar Vr S, Darisipudi MN, Steiger S, et al. Cathepsin S cleavage of protease-activated receptor-2 on endothelial cells promotes microvascular diabetes complications. J Am Soc Nephrol. 2016;27:1635–1649. 5. Zhao P, Lieu T, Barlow N, et al. Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. J Biol Chem. 2014;289: 27215–27234. 6. Sukhova GK, Zhang Y, Pan JH, et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;111:897–906. 7. Jobs E, Ingelsson E, Riserus U, et al. Association between serum cathepsin S and mortality in older adults. JAMA. 2011;306:1113–1121. 8. Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15: 203–216. 9. Rupanagudi KV, Kulkarni OP, Lichtnekert J, et al. Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming. Ann Rheum Dis. 2015;74: 452–463.
935