Diabetes Volume 63, June 2014
1829
Usha Panchapakesan and Carol A. Pollock
DPP-4 Inhibitors— Renoprotection in Diabetic Nephropathy? Diabetes 2014;63:1829–1830 | DOI: 10.2337/db14-0366
of diabetes enables the evaluation of the effects of the DPP-4 inhibitor independent of glycemic control. This is important because DPP-4 inhibitors will not have a significant hypoglycemic effect due to the lack of a significant insulin response mediated by GLP-1. As a result, the new findings provide information regarding renal benefit of linagliptin independent of glycemic control. In diabetic nephropathy, the fibrotic pathways that lead to scarring and kidney failure are mediated primarily through transforming growth factor-b (TGF-b). Antifibrotic strategies targeting TGF-b have been limited. Hence, the findings of Kanasaki et al. are highly relevant from a clinical point of view because of their potential as an antifibrotic agent in patients with diabetes. We have previously shown that the cation-independent mannose 6-phosphate receptor (CIM6PR) is central to the activation process of TGF-b1 in human kidney proximal tubular cells exposed to high glucose (2). We also have shown that linagliptin interferes with the conversion of latent to active TGF-b in human kidney proximal tubular cells and downstream fibrotic markers (3). Given that DPP-4 and CIM6PR colocalize on the cell membrane, it is highly likely that the mechanism by which linagliptin exerts its antifibrotic effect is through interrupting this protein–protein interaction and thereby reducing the activation of TGF-b. This can be confirmed with the use of proximity ligation assays, a technique used to directly observe individual endogenous protein complexes in situ (4). A schematic diagram summarizing this concept is shown in Fig. 1. Kanasaki et al. confirmed the TGF-b/miRNA 29 interaction that resulted in EndMT as a mechanism of fibrosis. However, it should be acknowledged that multiple miRNA families have been implicated in diabetic nephropathy. These include, but are not limited to, miRNA 200, 192, and 21. All are regulated by TGF-b1, but given the cell-specific interactions of miRNA and the
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, New South Wales, Australia
© 2014 by the American Diabetes Association. See http://creativecommons.org /licenses/by-nc-nd/3.0/ for details.
Corresponding author: Usha Panchapakesan, usha.panchapakesan@sydney .edu.au.
See accompanying article, p. 2120.
COMMENTARY
There is no doubt that rates of chronic kidney disease are escalating and that this rise is the main contributor to the increasing prevalence of diabetic nephropathy. It is also clear that the increase in kidney failure continues despite tight blood glucose and blood pressure control, as well as renin-angiotensin system blockade. In response, research into novel therapies to treat diabetic nephropathy is expanding, but to date nothing has translated into clinical use. The dipeptidyl peptidase-4 (DPP-4) inhibitors are oral, weight-neutral hypoglycemic drugs used to treat patients with type 2 diabetes. DPP-4 cleaves polypeptides with a proline/alanine in the penultimate position at the aminoterminal position. Hence, the net physiologic effect is a complex interplay between the resulting substrate/product profile in a particular disease milieu (rather than a specific signaling pathway). Cleaved substrates may either be activated, inactivated, or bear no functional relevance. DPP-4 inhibitors lower blood glucose levels by raising the half-life of short-lived endogenous incretins, such as GLP-1 and glucose-dependent insulinotropic polypeptide. However, the ability of DPP-4 to cleave a host of additional membrane-bound substrates that exert nonenzymatic properties by interacting or colocalizing with other membrane proteins/receptors suggests it may be a novel and exciting therapeutic target in diabetic nephropathy. In this issue, Kanasaki et al. (1) investigate the antifibrotic effect of linagliptin in a type 1 model of diabetic nephropathy. This study demonstrates that after 4 weeks linagliptin ameliorated diabetic kidney fibrosis, an observation that occurred in association with the inhibition of endothelial-to-mesenchymal transition (EndMT) and the restoration of microRNA (miRNA) 29s. An important aspect of this study is the use of a type 1 model of diabetes with streptozotocin. An insulin-deficient model
1830
Diabetes Volume 63, June 2014
Commentary
Figure 1—Schematic demonstrating the concept that the interaction between CIM6PR and DPP-4 is involved in the antifibrotic effects of linagliptin in kidneys. A: In normal glucose conditions, membrane CIM6PR and DPP-4 have minimal interaction. B: In high-glucose conditions, the interaction is increased and there is resulting activation of the TGF-b pathway and fibrosis. C: Linagliptin (L) prevents the high glucose–induced CIM6PR and DPP-4 interaction and resultant activation of the TGF-b pathway. The exact mechanism of how linagliptin does this remains unclear.
involvement of multiple cells in addition to endothelial cells that contribute to fibrosis in the kidney, further investigation of the interaction of DPP-4 inhibitors with tubular cells and podocytes is warranted. Ideally, such studies should include multiple DPP-4 inhibitors as it is possible that urinary excretion may modify the proteolytic activity of membrane-bound proteins expressed in the apical membrane of the proximal tubule and hence modify renal function as a consequence. The study by Kanasaki et al. (1) adds to the existing body of knowledge that in people with diabetes, DPP-4 inhibitors may provide additional renoprotection independent of glucose lowering. This is consistent with our own studies and also with the antifibrotic effects of DPP-4 inhibitors that have been demonstrated in other organs such as the liver (5). Clinical trials evaluating linagliptin and renal end points have commenced with the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk (CARMELINA) study, which will include more than 8,000 adults with type 2 diabetes. In this trial, the primary end point is time to first occurrence of cardiovascular death (including fatal stroke and fatal myocardial infarction), nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina pectoris. The renal outcome will be measured as a composite of renal death, sustained end-stage
renal disease, and sustained decrease of $50% estimated glomerular filtration rate. The outcome of this trial will provide much awaited information on whether DPP-4 inhibitors have the potential to be antifibrotic. Duality of Interest. U.P. and C.A.P. have been recipients of funding from Boehringer Ingelheim Germany. No other potential conflicts of interest relevant to this article were reported. References 1. Kanasaki K, Shi S, Kanasaki M, et al. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 2014; 63:2120–2131 2. Wong MG, Panchapakesan U, Qi W, Silva DG, Chen XM, Pollock CA. Cationindependent mannose 6-phosphate receptor inhibitor (PXS25) inhibits fibrosis in human proximal tubular cells by inhibiting conversion of latent to active TGFbeta1. Am J Physiol Renal Physiol 2011;301:F84–F93 3. Panchapakesan U, Gross S, Gangadharan Komala M, Pegg K, Pollock C. DPP4 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy? J Diabetes Metab 2013;S9:007 4. Söderberg O, Gullberg M, Jarvius M, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 2006;3: 995–1000 5. Kaji K, Yoshiji H, Ikenaka Y, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol 2014;49:481–491
1829
Usha Panchapakesan and Carol A. Pollock
DPP-4 Inhibitors— Renoprotection in Diabetic Nephropathy? Diabetes 2014;63:1829–1830 | DOI: 10.2337/db14-0366
of diabetes enables the evaluation of the effects of the DPP-4 inhibitor independent of glycemic control. This is important because DPP-4 inhibitors will not have a significant hypoglycemic effect due to the lack of a significant insulin response mediated by GLP-1. As a result, the new findings provide information regarding renal benefit of linagliptin independent of glycemic control. In diabetic nephropathy, the fibrotic pathways that lead to scarring and kidney failure are mediated primarily through transforming growth factor-b (TGF-b). Antifibrotic strategies targeting TGF-b have been limited. Hence, the findings of Kanasaki et al. are highly relevant from a clinical point of view because of their potential as an antifibrotic agent in patients with diabetes. We have previously shown that the cation-independent mannose 6-phosphate receptor (CIM6PR) is central to the activation process of TGF-b1 in human kidney proximal tubular cells exposed to high glucose (2). We also have shown that linagliptin interferes with the conversion of latent to active TGF-b in human kidney proximal tubular cells and downstream fibrotic markers (3). Given that DPP-4 and CIM6PR colocalize on the cell membrane, it is highly likely that the mechanism by which linagliptin exerts its antifibrotic effect is through interrupting this protein–protein interaction and thereby reducing the activation of TGF-b. This can be confirmed with the use of proximity ligation assays, a technique used to directly observe individual endogenous protein complexes in situ (4). A schematic diagram summarizing this concept is shown in Fig. 1. Kanasaki et al. confirmed the TGF-b/miRNA 29 interaction that resulted in EndMT as a mechanism of fibrosis. However, it should be acknowledged that multiple miRNA families have been implicated in diabetic nephropathy. These include, but are not limited to, miRNA 200, 192, and 21. All are regulated by TGF-b1, but given the cell-specific interactions of miRNA and the
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, New South Wales, Australia
© 2014 by the American Diabetes Association. See http://creativecommons.org /licenses/by-nc-nd/3.0/ for details.
Corresponding author: Usha Panchapakesan, usha.panchapakesan@sydney .edu.au.
See accompanying article, p. 2120.
COMMENTARY
There is no doubt that rates of chronic kidney disease are escalating and that this rise is the main contributor to the increasing prevalence of diabetic nephropathy. It is also clear that the increase in kidney failure continues despite tight blood glucose and blood pressure control, as well as renin-angiotensin system blockade. In response, research into novel therapies to treat diabetic nephropathy is expanding, but to date nothing has translated into clinical use. The dipeptidyl peptidase-4 (DPP-4) inhibitors are oral, weight-neutral hypoglycemic drugs used to treat patients with type 2 diabetes. DPP-4 cleaves polypeptides with a proline/alanine in the penultimate position at the aminoterminal position. Hence, the net physiologic effect is a complex interplay between the resulting substrate/product profile in a particular disease milieu (rather than a specific signaling pathway). Cleaved substrates may either be activated, inactivated, or bear no functional relevance. DPP-4 inhibitors lower blood glucose levels by raising the half-life of short-lived endogenous incretins, such as GLP-1 and glucose-dependent insulinotropic polypeptide. However, the ability of DPP-4 to cleave a host of additional membrane-bound substrates that exert nonenzymatic properties by interacting or colocalizing with other membrane proteins/receptors suggests it may be a novel and exciting therapeutic target in diabetic nephropathy. In this issue, Kanasaki et al. (1) investigate the antifibrotic effect of linagliptin in a type 1 model of diabetic nephropathy. This study demonstrates that after 4 weeks linagliptin ameliorated diabetic kidney fibrosis, an observation that occurred in association with the inhibition of endothelial-to-mesenchymal transition (EndMT) and the restoration of microRNA (miRNA) 29s. An important aspect of this study is the use of a type 1 model of diabetes with streptozotocin. An insulin-deficient model
1830
Diabetes Volume 63, June 2014
Commentary
Figure 1—Schematic demonstrating the concept that the interaction between CIM6PR and DPP-4 is involved in the antifibrotic effects of linagliptin in kidneys. A: In normal glucose conditions, membrane CIM6PR and DPP-4 have minimal interaction. B: In high-glucose conditions, the interaction is increased and there is resulting activation of the TGF-b pathway and fibrosis. C: Linagliptin (L) prevents the high glucose–induced CIM6PR and DPP-4 interaction and resultant activation of the TGF-b pathway. The exact mechanism of how linagliptin does this remains unclear.
involvement of multiple cells in addition to endothelial cells that contribute to fibrosis in the kidney, further investigation of the interaction of DPP-4 inhibitors with tubular cells and podocytes is warranted. Ideally, such studies should include multiple DPP-4 inhibitors as it is possible that urinary excretion may modify the proteolytic activity of membrane-bound proteins expressed in the apical membrane of the proximal tubule and hence modify renal function as a consequence. The study by Kanasaki et al. (1) adds to the existing body of knowledge that in people with diabetes, DPP-4 inhibitors may provide additional renoprotection independent of glucose lowering. This is consistent with our own studies and also with the antifibrotic effects of DPP-4 inhibitors that have been demonstrated in other organs such as the liver (5). Clinical trials evaluating linagliptin and renal end points have commenced with the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk (CARMELINA) study, which will include more than 8,000 adults with type 2 diabetes. In this trial, the primary end point is time to first occurrence of cardiovascular death (including fatal stroke and fatal myocardial infarction), nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina pectoris. The renal outcome will be measured as a composite of renal death, sustained end-stage
renal disease, and sustained decrease of $50% estimated glomerular filtration rate. The outcome of this trial will provide much awaited information on whether DPP-4 inhibitors have the potential to be antifibrotic. Duality of Interest. U.P. and C.A.P. have been recipients of funding from Boehringer Ingelheim Germany. No other potential conflicts of interest relevant to this article were reported. References 1. Kanasaki K, Shi S, Kanasaki M, et al. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 2014; 63:2120–2131 2. Wong MG, Panchapakesan U, Qi W, Silva DG, Chen XM, Pollock CA. Cationindependent mannose 6-phosphate receptor inhibitor (PXS25) inhibits fibrosis in human proximal tubular cells by inhibiting conversion of latent to active TGFbeta1. Am J Physiol Renal Physiol 2011;301:F84–F93 3. Panchapakesan U, Gross S, Gangadharan Komala M, Pegg K, Pollock C. DPP4 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy? J Diabetes Metab 2013;S9:007 4. Söderberg O, Gullberg M, Jarvius M, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 2006;3: 995–1000 5. Kaji K, Yoshiji H, Ikenaka Y, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol 2014;49:481–491
