Chronic treatment with the (iso-)glutaminyl cyclase inhibitor PQ529 is a novel and effective approach for glomerulonephr
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ORIGINAL ARTICLE
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 Received: 18 May 2020 / Accepted: 29 October 2020 # The Author(s) 2020
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 antiglomerular 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. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients. Keywords QC/isoQC inhibitor . PQ529 . CCL2/CCR2 axis . Glomerulonephritis . Chronic kidney disease
Introduction Chronic kidney disease (CKD) is a condition characterized by the poor long-term function of the kidneys. CKD is reportedly quite prevalent, and over 10% of the adult population in * Naotoshi Kanemitsu [email protected] 1
Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan
2
Corporate Advocacy, Astellas Pharma Inc., Chuo-ku, Tokyo 103-8411, Japan
3
Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki 305-8585, Japan
4
Astellas Innovation Management LLC, 1030 Massachusetts Ave. Suite 310, Cambridge, MA 02138, USA
developed countries is estimated to have some degree of CKD (Lopez-Novoa et al. 2010). CKD is usually caused by other conditions that place strain on the kidneys, often resulting from a combination
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