Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition
| Autor: | Shoko Ohno, Naoki Mochizuki, Haruko Watanabe-Takano, Yugo Kanai, Takashige Kuwabara, Motoko Yanagita, Akira Ishii, Nobuyuki Takahashi, Takaya Handa, Akihiro Yasoda, Masashi Mukoyama, Keita P. Mori, Hideki Yokoi |
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| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Male medicine.medical_specialty medicine.drug_class Pyridines Science p38 mitogen-activated protein kinases Muscle Proteins Mice Transgenic p38 Mitogen-Activated Protein Kinases Article Podocyte chemistry.chemical_compound Mice Internal medicine medicine Natriuretic peptide Animals RNA Messenger Protein kinase A Receptor Cyclic guanosine monophosphate Protein Kinase Inhibitors Mice Knockout Mice Inbred BALB C Multidisciplinary Kidney diseases Podocytes NPR1 Up-Regulation Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Endocrinology chemistry Doxorubicin Nephrology Medicine Pyrazoles Receptors Atrial Natriuretic Factor Signal Transduction Transcription Factors |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
| ISSN: | 2045-2322 |
| Popis: | Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury. |
| Databáze: | OpenAIRE |
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