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In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy. However, how cellular mechanics and metabolism are connected remains unclear. A multi-disciplinary approach was employed: the fibrotic kidney disease models were induced by renal ischemia-reperfusion injury and unilateral ureteral obstruction in Calponin 2 (CNN2) knockdown mice. Proteomics, bioinformatics, and in vivo and in vitro molecular experimental pathology studies were performed. Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated events in the fibrotic kidneys. As a prominent actin stabilizer, CNN2 was predominantly expressed in fibroblasts and pericytes. In CKD patients, CNN2 levels was markedly induced in blood. In mice, CNN2 knockdown preserves kidney function and alleviates fibrosis. Global proteomics profiled that CNN2 knockdown enhanced the activities of the key rate-limiting enzymes and regulators of fatty acid oxidation (FAO) in the diseased kidneys. Inhibiting carnitine palmitoyltransferase 1α in the FAO pathway resulted in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. Bioinformatics and chromatin immunoprecipitation showed that CNN2 interactor, estrogen receptor 2 (ESR2), binds peroxisome proliferator-activated receptor-α (PPARα) to transcriptionally regulate FAO downstream target genes expression amid kidney fibrosis. In vitro , ESR2 knockdown repressed the mRNA levels of PPARα and the key genes in the FAO pathway. Conversely, activation of PPARα reduced CNN2-induced matrix inductions. Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis. • Serum CNN2 was increased in CKD patients. • Knockdown of CNN2 alleviated kidney fibrosis in CKD models. • Knockdown of CNN2 enhanced FAO and reduced lipid accumulation after CKD. • Knockdown of CNN2 preserved kidney functions once CPT-1α was inhibited. • CNN2 interacts with ESR2 to transcriptionally modulate the activity of PPARα. [ABSTRACT FROM AUTHOR]

A series of experiments was carried out to assess whether the «defensive» pattern of female parental attack towards sexually naive male conspecific intruders, in which there is no inhibition against biting vulnerable areas of the intruder's body, could function as a deterrent to infanticide. Primiparous lactating mice (Mus domesticus) which had not previously displayed parental attack showed clearly differentiated patterns of biting attack when confronting sexually naive male and female conspecific intruders, respectively. Males intruders were more prone to kill pups than were female counterparts, and this behaviour was facilitated in the absence of the mother. Remarkably, lactating females simultaneously confronting a virgin female and a sexually naive male intruder attacked only the latter animal. These data suggest that lactating female aggression serves as a counterstrategy to male infanticide. Nevertheless the mother's aggressive behaviour delayed but rarely thwarted the killing of pups by males that had dominated the female and that were characterized by high levels of social aggression in previous intermale aggression tests. Maternal attack was successful in defending the litter from those males that were incapable of defeating the lactating female and that were characterized by low levels of intermale aggression. Consequently, maternal aggression might also function, as a by-product, to prevent reproduction by males of poor fighting ability. The hypothesis that in this context female aggressive behaviour towards the interloper male could also be involved in intersexual selection is discussed. [ABSTRACT FROM PUBLISHER]

Lactating mice respond differently to male and female conspecific intruders, displaying defensive attack towards the former and offensive attack towards the latter. Two studies are reported in which the effects of naloxone on this differential response pattern were assessed. In the first study, lactating residents were pretreated with saline or naloxone (0.5, 2.5 mg/kg) and consecutively confronted with intruders of differing sex. Results suggested that attack (offensive) against female conspecific is more sensitive to the inhibitory effects of opiate-receptor blockade than attack (defensive) on males. This conclusion was strengthened in a follow-up study, in which independent groups of lactating residents were used to further examine the effects of naloxone (0.5 mg/kg) on response to male and female intrusion. Analysis indicated that this low dose of naloxone significantly inhibited attack on female, but not on male, intruders. Indeed, in response to male, but not to female, intrusion, naloxone-treated residents showed a significant increase in fear-related behaviour. Findings are discussed in relation to the motivational differences in the response of lactating mice to intruders of differing sex and to possible mechanisms underlying the reported differential effects of opiate-receptor blockade. [ABSTRACT FROM AUTHOR]

Objective: We assessed the lifetime risk of cardiovascular disease (CVD) among individuals with and without obesity and diabetes. Research Design and Methods: Participants were drawn from the original and offspring cohorts of the Framingham Heart Study. Lifetime (30-year) risk of CVD was assessed using a modified Kaplan-Meier approach adjusting for the competing risk of death, beginning from age 50 years. Results: Over 30 years, the lifetime risk of CVD among women with diabetes was 54.8% among normal-weight women and 78.8% among obese women. Among normal-weight men with diabetes, the lifetime risk of CVD was 78.6%, whereas it was 86.9% among obese men. Conclusions: The lifetime risk of CVD among individuals with diabetes is high, and this relationship is further accentuated with increasing adiposity.