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Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition.
- Source :
-
Scientific reports [Sci Rep] 2021 Nov 08; Vol. 11 (1), pp. 21835. Date of Electronic Publication: 2021 Nov 08. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2021. The Author(s).)
- Subjects :
- Animals
Disease Models, Animal
Doxorubicin toxicity
Kidney Diseases chemically induced
Kidney Diseases pathology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Muscle Proteins deficiency
Muscle Proteins genetics
Podocytes drug effects
Podocytes metabolism
Podocytes pathology
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Pyridines pharmacology
RNA, Messenger genetics
RNA, Messenger metabolism
Receptors, Atrial Natriuretic Factor metabolism
Signal Transduction drug effects
Transcription Factors deficiency
Transcription Factors genetics
Up-Regulation
p38 Mitogen-Activated Protein Kinases metabolism
Kidney Diseases metabolism
Muscle Proteins metabolism
Transcription Factors metabolism
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 34750411
- Full Text :
- https://doi.org/10.1038/s41598-021-01095-8