Background Intramuscular fat(IMF)content is a critical indicator of pork quality,and abnormal IMF is also relevant to human disease as well as aging.Although N6-methyladenosine(m^(6)A)RNA modification was recently fou...Background Intramuscular fat(IMF)content is a critical indicator of pork quality,and abnormal IMF is also relevant to human disease as well as aging.Although N6-methyladenosine(m^(6)A)RNA modification was recently found to regulate adipogenesis in porcine intramuscular fat,however,the underlying molecular mechanisms was still unclear.Results In this work,we collected 20 longissimus dorsi muscle samples with high(average 3.95%)or low IMF content(average 1.22%)from a unique heterogenous swine population for m^(6)A sequencing(m^(6)A-seq).We discovered 70genes show both differential RNA expression and m^(6)A modification from high and low IMF group,including ADIPOQ and SFRP1,two hub genes inferred through gene co-expression analysis.Particularly,we observed ADIPOQ,which contains three m^(6)A modification sites within 3’untranslated and protein coding region,could promote porcine intramuscular preadipocyte differentiation in an m^(6)A-dependent manner.Furthermore,we found the YT521-B homology domain family protein 1(YTHDF1)could target and promote ADIPOQ mRNA translation.Conclusions Our study provided a comprehensive profiling of m^(6)A methylation in porcine longissimus dorsi muscle and characterized the involvement of m^(6)A epigenetic modification in the regulation of ADIPOQ mRNA on IMF deposition through an m^(6)A-YTHDF1-dependent manner.展开更多
Chronic kidney disease(CKD)and heart failure(HF)are highly prevalent,aggravate each other,and account for substantial mortality.However,the mechanisms underlying cardiorenal interaction and the role of kidney afferent...Chronic kidney disease(CKD)and heart failure(HF)are highly prevalent,aggravate each other,and account for substantial mortality.However,the mechanisms underlying cardiorenal interaction and the role of kidney afferent nerves and their precise central pathway remain limited.Here,we combined virus tracing techniques with optogenetic techniques to map a polysynaptic central pathway linking kidney afferent nerves to subfornical organ(SFO)and thereby to paraventricular nucleus(PVN)and rostral ventrolateral medulla that modulates sympathetic outflow.This kidney-brain neural circuit was overactivated in mouse models of CKD or HF and subsequently enhanced the sympathetic discharge to both the kidney and the heart in each model.Interruption of the pathway by kidney deafferentation,selective deletion of angiotensin II type 1a receptor(AT1a)in SFO,or optogenetic silence of the kidney-SFO or SFO-PVN projection decreased the sympathetic discharge and lessened structural damage and dysfunction of both kidney and heart in models of CKD and HF.Thus,kidney afferent nerves activate a kidney-brain neural circuit in CKD and HF that drives the sympathetic nervous system to accelerate disease progression in both organs.These results demonstrate the crucial role of kidney afferent nerves and their central connections in engaging cardiorenal interactions under both physiological and disease conditions.This suggests novel therapies for CKD or HF targeting this kidney-brain neural circuit.展开更多
The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedge...The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog(Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease(CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelialmesenchymal communication(EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.展开更多
基金supported by funds from the National Natural Science Foundation of China (Grant No.U21A20249)China Postdoctoral Science Foundation (2022 M712794)。
文摘Background Intramuscular fat(IMF)content is a critical indicator of pork quality,and abnormal IMF is also relevant to human disease as well as aging.Although N6-methyladenosine(m^(6)A)RNA modification was recently found to regulate adipogenesis in porcine intramuscular fat,however,the underlying molecular mechanisms was still unclear.Results In this work,we collected 20 longissimus dorsi muscle samples with high(average 3.95%)or low IMF content(average 1.22%)from a unique heterogenous swine population for m^(6)A sequencing(m^(6)A-seq).We discovered 70genes show both differential RNA expression and m^(6)A modification from high and low IMF group,including ADIPOQ and SFRP1,two hub genes inferred through gene co-expression analysis.Particularly,we observed ADIPOQ,which contains three m^(6)A modification sites within 3’untranslated and protein coding region,could promote porcine intramuscular preadipocyte differentiation in an m^(6)A-dependent manner.Furthermore,we found the YT521-B homology domain family protein 1(YTHDF1)could target and promote ADIPOQ mRNA translation.Conclusions Our study provided a comprehensive profiling of m^(6)A methylation in porcine longissimus dorsi muscle and characterized the involvement of m^(6)A epigenetic modification in the regulation of ADIPOQ mRNA on IMF deposition through an m^(6)A-YTHDF1-dependent manner.
基金supported by the Major International(Regional)Joint Research Project of the National Natural Science Foundation of China(81620108003 to F.F.H.)Program of Introducing Talents of Discipline to Universities,111 Plan(D18005 to F.F.H.)+2 种基金The National Natural Science Foundation of China(Key Program)(82030022 to F.F.H.)Guangdong key program of precision medicine(2022 to F.F.H.)the National Natural Science Foundation of China(82270776,81922014,81870473 to W.C.).
文摘Chronic kidney disease(CKD)and heart failure(HF)are highly prevalent,aggravate each other,and account for substantial mortality.However,the mechanisms underlying cardiorenal interaction and the role of kidney afferent nerves and their precise central pathway remain limited.Here,we combined virus tracing techniques with optogenetic techniques to map a polysynaptic central pathway linking kidney afferent nerves to subfornical organ(SFO)and thereby to paraventricular nucleus(PVN)and rostral ventrolateral medulla that modulates sympathetic outflow.This kidney-brain neural circuit was overactivated in mouse models of CKD or HF and subsequently enhanced the sympathetic discharge to both the kidney and the heart in each model.Interruption of the pathway by kidney deafferentation,selective deletion of angiotensin II type 1a receptor(AT1a)in SFO,or optogenetic silence of the kidney-SFO or SFO-PVN projection decreased the sympathetic discharge and lessened structural damage and dysfunction of both kidney and heart in models of CKD and HF.Thus,kidney afferent nerves activate a kidney-brain neural circuit in CKD and HF that drives the sympathetic nervous system to accelerate disease progression in both organs.These results demonstrate the crucial role of kidney afferent nerves and their central connections in engaging cardiorenal interactions under both physiological and disease conditions.This suggests novel therapies for CKD or HF targeting this kidney-brain neural circuit.
基金supported by the National Natural Science Foundation of China(81130011,81370839,81521003)Guangdong Science Foundation(2014A030312014)+2 种基金Guangzhou Projects Grant(15020025)American Heart Association FTF(16990086)National Institutes of Health Grants(DK064005,DK091239,DK106049)
文摘The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog(Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease(CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelialmesenchymal communication(EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.