Context. Mergers of two stellar origin black holes are a prime source of gravitational waves and are under intensive investigation. One crucial ingredient in their modeling has been neglected: pair-instability pulsation supernovae with associated severe mass loss may suppress the formation of massive black holes, decreasing black hole merger rates for the highest black hole masses. Aims. We demonstrate the effects of pair-instability pulsation supernovae on merger rate and mass using populations of double black hole binaries formed through the isolated binary classical evolution channel. Methods. The mass loss from pair-instability pulsation supernova is estimated based on existing hydrodynamical calculations. This mass loss is incorporated into the StarTrack population synthesis code. StarTrack is used to generate double black hole populations with and without pair-instability pulsation supernova mass loss. Results. The mass loss associated with pair-instability pulsation supernovae limits the Population I/II stellar-origin black hole mass to 50 M ⊙ , in tension with earlier predictions that the maximum black hole mass could be as high as 100 M ⊙ . In our model, neutron stars form with mass 1-2 M ⊙ , then we encounter the first mass gap at 2-5 M ⊙ with an absence of compact objects due to rapid supernova explosions, followed by the formation of black holes with mass 5-50 M ⊙ , with a second mass gap at 50-135 M ⊙ created by pairinstability pulsation supernovae and by pair-instability supernovae. Finally, black holes having masses above 135 M ⊙ may potentially form to arbitrarily high mass limited only by the extent of the initial mass function and the strength of stellar winds. Suppression of double black hole merger rates by pair-instability pulsation supernovae is negligible for our evolutionary channel. Our standard evolutionary model with the inclusion of pair-instability pulsation supernovae and pair-instability supernovae is fully consistent with the LIGO observations of black hole mergers: GW150914, GW151226, and LVT151012. The LIGO results are inconsistent with high ( 400 km s −1 ) BH natal kicks. We predict the detection of several, and up to as many as ∼ 60, BH-BH mergers with a total mass of 10-150 M ⊙ (most likely range: 20-80 M ⊙ ) in the forthcoming ∼ 60 effective days of the LIGO O2 observations, assuming the detectors reach the optimistic target O2 sensitivity. Conclusions.

TGF-␤/Smad signaling plays a role in fibrogenesis, but therapies targeting TGF-␤ are ineffective in treating renal fibrosis. Here, we explored the therapeutic potential of targeting TGF-␤-induced microRNA in the progression of renal fibrosis. Microarray analysis and real-time PCR revealed upregulation of miR-21 in tubular epithelial cells (TECs) in response to TGF-␤. Lack of Smad3, but not lack of Smad2, prevented cells from upregulating miR-21 in response to TGF-␤. In addition, Smad3-deficient mice were protected from upregulation of miR-21 and fibrosis in the unilateral ureteral obstruction model. In contrast, conditional knockout of Smad2 enhanced miR-21 expression and renal fibrosis. Furthermore, ultrasound-microbubble-mediated gene transfer of a miR-21-knockdown plasmid halted the progression of renal fibrosis in established obstructive nephropathy. In conclusion, these data demonstrate that Smad3, but not Smad2, signaling increases expression of miR-21, which promotes renal fibrosis. Inhibition of miR-21 may be a therapeutic approach to suppress renal fibrosis.

Aims/hypothesis As microRNA-21 (miR-21) plays a pathological role in fibrosis, we hypothesised that it may be a therapeutic target for diabetic nephropathy. Methods Abundance of miR-21 was examined in diabetic kidneys from db/db mice. The therapeutic potential of miR-21 in diabetic kidney injury was examined in db/db mice by an ultrasound-microbubble-mediated miR-21 small hairpin RNA transfer. In addition, the role and mechanisms of miR-21 in diabetic renal injury were examined in vitro under diabetic conditions in rat mesangial and tubular epithelial cell lines by overexpressing or downregulating miR-21.

OBJECTIVEAlthough Smad3 has been considered as a downstream mediator of transforming growth factor-β (TGF-β) signaling in diabetes complications, the role of Smad7 in diabetes remains largely unclear. The current study tests the hypothesis that Smad7 may play a protective role and has therapeutic potential for diabetic kidney disease.RESEARCH DESIGN AND METHODSProtective role of Smad7 in diabetic kidney disease was examined in streptozotocin-induced diabetic mice that have Smad7 gene knockout (KO) and in diabetic rats given Smad7 gene transfer using an ultrasound-microbubble-mediated technique.RESULTSWe found that mice deficient for Smad7 developed more severe diabetic kidney injury than wild-type mice as evidenced by a significant increase in microalbuminuria, renal fibrosis (collagen I, IV, and fibronectin), and renal inflammation (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], monocyte chemoattractant protein-1 [MCP-1], intracellular adhesion molecule-1 [ICAM-1], and macrophages). Further studies revealed that enhanced renal fibrosis and inflammation in Smad7 KO mice with diabetes were associated with increased activation of both TGF-β/Smad2/3 and nuclear factor-κB (NF-κB) signaling pathways. To develop a therapeutic potential for diabetic kidney disease, Smad7 gene was transferred into the kidney in diabetic rats by an ultrasound-microbubble-mediated technique. Although overexpression of renal Smad7 had no effect on levels of blood glucose, it significantly attenuated the development of microalbuminuria, TGF-β/Smad3-mediated renal fibrosis such as collagen I and IV and fibronectin accumulation and NF-κB/p65-driven renal inflammation including IL-1β, TNF-α, MCP-1, and ICAM-1 expression and macrophage infiltration in diabetic rats.CONCLUSIONSSmad7 plays a protective role in diabetic renal injury. Overexpression of Smad7 may represent a novel therapy for the diabetic kidney complication.

No abstract

No abstract

The mechanism by which TGF-β regulates renal inflammation and fibrosis is largely unclear; however, it is well accepted that its biological effects are mediated through Smad2 and Smad3 phosphorylation. Following activation, these Smads form heteromeric complex with Smad4 and translocate into the nucleus to bind and regulate the expression of target genes. Here we studied the roles of Smad4 to regulate TGF-β signaling in a mouse model of unilateral ureteral obstruction using conditional Smad4 knockout mice and in isolated Smad4 mutant macrophages and fibroblasts. Disruption of Smad4 significantly enhanced renal inflammation as evidenced by a greater CD45(+) leukocyte and F4/80(+) macrophage infiltration and upregulation of IL-1β, TNF-α, MCP-1, and ICAM-1 in the obstructed kidney and in IL-1β-stimulated macrophages. In contrast, deletion of Smad4 inhibited renal fibrosis and TGF-β1-induced collagen I expression by fibroblasts. Further studies showed that the loss of Smad4 repressed Smad7 transcription, leading to a loss of functional protein. This, in turn, inhibited IκBα expression but enhanced NF-κB activation, thereby promoting renal inflammation. Interestingly, deletion of Smad4 influenced Smad3-mediated promoter activities and the binding of Smad3 to the COL1A2 promoter, but not Smad3 phosphorylation and nuclear translocation, thereby inhibiting the fibrotic response. Thus, Smad4 may be a key regulator for the diverse roles of TGF-β1 in inflammation and fibrogenesis by interacting with Smad7 and Smad3 to influence their transcriptional activities in renal inflammation and fibrosis.

microRNA-29b (miR-29b) is known to be associated with TGF-β-mediated fibrosis, but the mechanistic action of miR-29b in liver fibrosis remains unclear and is warranted for investigation. We found that miR-29b was significantly downregulated in human and mice fibrotic liver tissues and in primary activated HSCs. miR-29b downregulation was directly mediated by Smad3 through binding to the promoter of miR-29b in hepatic stellate cell (HSC) line LX1, whilst miR-29b could in turn suppress Smad3 expression. miR-29b transduction in the liver of mice prevented CCl4 induced-fibrogenesis, concomitant with decreased expression of α-SMA, collagen I and TIMP-1. Ectopic expression of miR-29b in activated HSCs (LX-1, HSC-T6) inhibited cell viability and colony formation, and caused cell cycle arrest in G1 phase by downregulating cyclin D1 and p21cip1. Further, miR-29b induced apoptosis in HSCs mediated by caspase-9 and PARP. miR-29b inhibited its downstream effectors of PIK3R1 and AKT3 through direct targeting their 3′UTR regions. Moreover, knockdown of PIK3R1 or AKT3 suppressed α-SMA and collagen I and induced apoptosis in both HSCs and in mice. In conclusion, miR-29b prevents liver fibrogenesis by inhibiting HSC activation and inducing HSC apoptosis through inhibiting PI3K/AKT pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-29b.