The DPP4 inhibitor linagliptin ameliorated renal injury and accelerated resolution in a rat model of crescentic nephritis

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The DPP4 inhibitor linagliptin ameliorated renal injury and accelerated resolution in a rat model of crescentic nephritis (1)

Crescent formation is a histologic hallmark of severely damaged glomeruli occurring in different renal diseases but with the highest frequency in anti‐glomerular basement membrane nephritis, immune‐complex glomerulonephritis and pauci immune glomerulonephritis. high expression of dipeptidyl peptidase 4 (DPP‐4) in crescents in human biopsies with different forms of glomerulonephritis. DPP‐4 functions as an exopeptidase to cleave or inactivate several physiological substrates and also occurs as a membranous glycoprotein along with a circulating variant in blood. The role of renal DPP‐4 in the pathogenesis of glomerular diseases and therapeutic effects of DPP‐4 inhibition, such as linagliptin, beyond regulation of the glucose metabolism, is still unclear. DPP‐4 cleaves a wide range of other substrates including peptide hormones such as stromal‐derived factor 1 alpha (SDF‐1α; CXCL12 α) or monocyte chemoattractant protein 1 (MCP‐1 or CCL2).

Male Wistar Kyoto rats by a single intravenous tail vein injection of 30 μg of mouse monoclonal anti‐α4(IV)NC1 of rat anti‐glomerular basement membrane antibody in each regimen. The rats were killed under isoflurane anaesthesia on day 14 or 8 weeks after induction of glomerular basement membrane nephritis.

The DPP‐4 inhibitor linagliptin was used to block DPP‐4 activity, resulting in almost complete inhibition of detectable renal DPP‐4 activity 7 or 14 days after start of the treatment, without any effect on DPP‐4 expression. In addition, plasma DPP‐4 activity was strongly inhibited in linagliptin‐treated groups.

While therapeutic DPP‐4 inhibition starting after 1 week could only slightly but significantly reduce proteinuria and serum urea levels on Day 14, initial preventive treatment did not significantly lower proteinuria in the short‐term experiment. In the long‐term preventive linagliptin treatment group, proteinuria was lowered by more than 25% on Weeks 3–5 but did not reach the level of significance at endpoint on Week 8. Long‐term therapeutic linagliptin treatment was less efficient but also showed a tendency to lower proteinuria and serum urea levels. Serum creatinine was increased by less than 20% in this model with a tendency to reduce levels in the preventive long‐term DPP‐4 inhibitor group.

Linagliptin time dependently changed glomerular influx of ED1‐positive macrophages inglomerular basement membrane nephritis. At Day 14, glomerular ED1‐positive macrophages were significantly increased in the therapeutically treated group compared to the non‐treated nephritic group. In contrast, at Week 8, macrophage numbers tended to be lower in the preventive treatment group compared to untreated and therapeutically treated rats. The number of CD163‐positive M2‐like macrophages was very low, and there was no significant change due to treatment with the DPP‐4 inhibitor. Since the macrophage attracting chemokine MCP‐1 is a substrate for DPP‐4, MCP‐1 serum levels Induction of glomerular basement membrane nephritis significantly increased serum MCP‐1 without clear effect of linagliptin treatment.

Both preventive and therapeutic linagliptin treatment significantly reduced glomerular as well as cortical fibrosis in the long‐term experiment, as assessed by sirius red stain. In healthy glomeruli, myofibroblast marker SMA was absent but increased early after disease induction on Days 7 and 14 showing SMA‐positive cells within the crescents, on the glomerular tuft and the Bowman capsule); but the number was not changed by linagliptin treatment in the short‐term experiment.

This study is limited by focusing on selected DPP‐4 substrates and we cannot exclude that additional DPP‐4 substrates or interaction partners are involved. One key substrate of DPP‐4 is, for example, GLP‐1, but linagliptin effects on crescent formation mediated by the incretin GLP‐1 are unlikely since in humans neither podocytes nor parietal epithelial cells express the GLP‐1 receptor on their surface.

1. A.-L. Mayer, I. Scheitacker, N. Ebert, T. Klein, K. Amann, C. Daniel, The dipeptidyl peptidase 4 inhibitor linagliptin ameliorates renal injury and accelerated resolution in a rat model of crescentic nephritis. Br. J. Pharmacol. 178, 878–895 (2021).

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