Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition

• Published in: Scientific reports Vol. 11; no. 1; p. 21835
• Main Authors: Handa, Takaya, Mori, Keita P., Ishii, Akira, Ohno, Shoko, Kanai, Yugo, Watanabe-Takano, Haruko, Yasoda, Akihiro, Kuwabara, Takashige, Takahashi, Nobuyuki, Mochizuki, Naoki, Mukoyama, Masashi, Yanagita, Motoko, Yokoi, Hideki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 692/4022; 692/4022/1585; Animals; Cyclic GMP; Disease Models, Animal; Doxorubicin - toxicity; Gene expression; Guanylate cyclase; Humanities and Social Sciences; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidneys; Kinases; Macrophages; Male; MAP kinase; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Monocyte chemoattractant protein 1; multidisciplinary; Muscle Proteins - deficiency; Muscle Proteins - genetics; Muscle Proteins - metabolism; Nephropathy; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Peptides; Phenotypes; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Protein kinase; Protein Kinase Inhibitors - pharmacology; Pyrazoles - pharmacology; Pyridines - pharmacology; Receptors, Atrial Natriuretic Factor - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Science; Science (multidisciplinary); Signal Transduction - drug effects; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Transgenic mice; Up-Regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-01095-8

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.