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. 2021 Apr;394(4):751-761.
doi: 10.1007/s00210-020-02013-x. Epub 2021 Mar 29.

"V体育官网入口" Chronic treatment with the (iso-)glutaminyl cyclase inhibitor PQ529 is a novel and effective approach for glomerulonephritis in chronic kidney disease

Naotoshi Kanemitsu  1 , Fumiko Kiyonaga  2 , Kazuhiko Mizukami  3 , Kyoichi Maeno  3 , Takashi Nishikubo  4 , Hiroyuki Yoshida  3 , Hiroyuki Ito  3
Affiliations

V体育官网 - Chronic treatment with the (iso-)glutaminyl cyclase inhibitor PQ529 is a novel and effective approach for glomerulonephritis in chronic kidney disease

Naotoshi Kanemitsu et al. Naunyn Schmiedebergs Arch Pharmacol. 2021 Apr.

"VSports最新版本" Abstract

Glomeruli and renal tubule injury in chronic kidney disease (CKD) is reported to involve induction of macrophage activation through the CCL2/CCR2 axis. The effects of inhibitors of the CCL2/CCR2 axis, such as anti-CCL2 antibody and CCR2 antagonist, on kidney function in animal models or humans with kidney dysfunction have been demonstrated. The N-terminal glutamine on immature CCL2 is replaced with pyroglutamate (pE) by glutaminyl cyclase (QC) and isoQC. pE-CCL2 is stable and resistant to peptidases. We hypothesized that inhibiting QC/isoQC activity would lead to the degradation of CCL2, thereby ameliorating CKD and reducing kidney inflammation. To test this hypothesis, we investigated the renoprotective properties of the QC/isoQC inhibitor PQ529 in anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis Wistar Kyoto (WKY) rats. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. Correlations between the urinary protein level and serum or urinary CCL2 levels were confirmed in tested animals. Repeated administration of PQ529 significantly reduced the expression of CD68, a macrophage marker, in the kidney cortex and mononuclear infiltration into the tubulointerstitium. In addition, decreased levels of urinary KIM-1, β2 microglobulin, and clusterin were detected, suggesting the inhibition of inflammation in both the proximal and distal tubules. These results suggest that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis VSports手机版. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients. .

Keywords: CCL2/CCR2 axis; Chronic kidney disease; Glomerulonephritis; PQ529; QC/isoQC inhibitor V体育安卓版. .

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Conflict of interest statement

The authors declare no conflict of interest other than being employees of Astellas Pharma Inc V体育ios版. that could be perceived as prejudicing the impartiality of the research reported.

Figures

Fig. 1
Fig. 1
Pharmacokinetics and pharmacodynamics of PQ529 in Wistar and WKY rats and effect of repeated administration of PQ529 on the urinary protein excretion in anti-GBM-induced glomerulonephritis rats. a Time course of changes in the plasma concentration of the unchanged PQ529 (30 and 100 mg/kg) in male Wistar rats. b Time course of changes in the plasma concentration of pE-CCL2 after the administration of PQ529 (30 and 100 mg/kg) to WKY rats. c PQ529 was orally administered to anti-GBM-induced glomerulonephritis rats twice daily for 3 weeks. Data are expressed as the mean ± S.D. for a three Wistar rats and b five WKY rats per sampling point and c 10 WKY rats per group. The results are expressed as the mean ± standard deviation (S.D.). Significant differences between two groups were assessed using Student’s t test, while those among multiple groups were assessed using a one-way analysis of variance followed by Dunnett’s multiple comparisons test as a post hoc test. *p < 0.05 vs. normal group, #p < 0.05 vs. vehicle group
Fig. 2
Fig. 2
Effect of repeated administration of PQ529 on a serum, b urine, and c kidney CCL2 and correlation between d serum, e urine, and f kidney CCL2 and urine protein-to-creatinine ratio in anti-GBM-induced glomerulonephritis rats. PQ529 was orally administered to anti-GBM-induced glomerulonephritis rats twice daily for 3 weeks. Data are expressed as the mean ± S.D. for 10 animals per group. The results are expressed as the mean ± standard deviation (S.D.). Significant differences between two groups were assessed using Student’s t test, while those among multiple groups were assessed using a one-way analysis of variance followed by Dunnett’s multiple comparisons test as a post hoc test. Correlations were analyzed using Pearson’s rank correlation. *p < 0.05 vs. normal group, #p < 0.05 vs. vehicle group
Fig. 3
Fig. 3
Effect of repeated administration of PQ529 on renal a CD68 and b CCL2 expression in anti-GBM-induced glomerulonephritis rats. PQ529 was orally administered to anti-GBM-induced glomerulonephritis rats twice daily for 3 weeks. Data are expressed as the mean ± S.D. for 10 animals per group. The results are expressed as the mean ± standard deviation (S.D.). Significant differences between two groups were assessed using Student’s t test, while those among multiple groups were assessed using a one-way analysis of variance followed by Dunnett’s multiple comparisons test as a post hoc test. *p < 0.05 vs. normal group, #p < 0.05 vs. vehicle group
Fig. 4
Fig. 4
Effect of repeated administration of PQ529 on mononuclear cell infiltration in glomerulonephritis rats. PQ529 was orally administered to glomerulonephritis rats twice daily for 3 weeks. Data are expressed as the mean ± S.D. for 10 animals per group. Significant differences between two groups were assessed using Student’s t test, while those among multiple groups were assessed using a one-way analysis of variance followed by Dunnett’s multiple comparisons test as a post hoc test. *p < 0.05 vs. normal group, #p < 0.05 vs. vehicle group
Fig. 5
Fig. 5
Effect of repeated administration of PQ529 on a glomerulosclerosis and b tubulointerstitial damage in glomerulonephritis rats and representative light micrographs of renal tissues obtained from c, d normal (semiquantitative scores of glomerulosclerosis, tubulointerstitial damage: 0, 0), e, f glomerulonephritis (scores: 3, 3), and g, h PQ529 (100 mg/kg)-treated rats (scores: 2, 1). Magnification: left, × 40 (PAS stain); right, × 10 (H&E stain). PQ529 was orally administered to glomerulonephritis rats twice daily for 3 weeks. Data are expressed as the median for 10 animals per group. Histopathological nonparametric scores were compared using a Mann–Whitney test to analyze differences between two groups, while a nonparametric Kruskal–Wallis analysis of variance followed by Dunn’s multiple comparisons test was used for comparisons among multiple groups. *p < 0.05 vs. normal group, #p < 0.05 vs. vehicle group
Fig. 6
Fig. 6
Effect of repeated administration of PQ529 on the urinary a KIM-1, b β2 microglobulin, and c clusterin levels and d kidney IFN-γ levels in anti-GBM-induced glomerulonephritis rats. PQ529 was orally administered to anti-GBM-induced glomerulonephritis rats twice daily for 3 weeks. Data are expressed as the mean ± S.D. for 10 animals per group. Significant differences between two groups were assessed using Student’s t test, while those among multiple groups were assessed using a one-way analysis of variance followed by Dunnett’s multiple comparisons test as a post hoc test. *p < 0.05 vs. normal group, #p < 0.05 vs. vehicle group
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