N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a natural inhibitor of pluripotent hematopoietic stem cell proliferation, has been suggested as capable of promoting an angiogenic response. We studied whether Ac-SDKP stimulates endothelial cell proliferation, migration, and tube formation; enhances angiogenic response in the rat cornea after implantation of a tumor spheroid; and increases capillary density in rat hearts with myocardial infarction (MI). In vitro, an immortal BALB/c mouse aortic endothelial 22106 cell line was used to determine the effects of Ac-SDKP on endothelial cell proliferation and migration and tube formation. In vivo, a 9L-gliosarcoma cell spheroid (250-300 microm in diameter) was implanted in the rat cornea and vehicle or Ac-SDKP (800 microg.kg(-1).day(-1) ip) infused via osmotic minipump. Myocardial capillary density was studied in rats with MI given either vehicle or Ac-SDKP. We found that Ac-SDKP 1) stimulated endothelial cell proliferation and migration and tube formation in a dose-dependent manner, 2) enhanced corneal neovascularization, and 3) increased myocardial capillary density. Endothelial cell proliferation and angiogenesis stimulated by Ac-SDKP could be beneficial in cardiovascular diseases such as hypertension and MI. Furthermore, because Ac-SDKP is mainly cleaved by ACE, it may partially mediate the cardioprotective effect of ACE inhibitors.

Abstract-Kinins exert cardioprotective effects via 2 G-protein-coupled receptors, B 1 and B 2. Using B 1 kinin receptor gene knockout mice (B 1 Ϫ/Ϫ ), we tested the hypotheses that the B 1 receptor plays an important role in preservation of cardiac function, whereas lack of B 1 may accelerate cardiac remodeling and dysfunction after myocardial infarction, and that B 2 receptors may compensate for lack of B 1 , whereas blockade of B 2 receptors in B 1 Ϫ/Ϫ mice may cause further deterioration of cardiac function and remodeling. Female B 1 Ϫ/Ϫ mice and wild-type controls (C57BL/6J, B 1 ϩ/ϩ ) underwent sham surgery or myocardial infarction and were treated with either vehicle or B 2 -antagonist (icatibant, 500 g/kg per day, subcutaneous) for 8 weeks. We found that in sham myocardial infarction, B 1 Ϫ/Ϫ mice had a larger left ventricular diastolic chamber dimension both initially and at 4 to 8 weeks compared with B 1 ϩ/ϩ . Left ventricular mass and myocyte size were also larger in B 1 Ϫ/Ϫ with sham operation than in B 1 ϩ/ϩ , although cardiac function did not differ between strains. After myocardial infarction, cardiac remodeling and function were similar in both strains, although B 1 Ϫ/Ϫ mice tended to have lower blood pressure. Blockade of B 2 receptors tended to worsen cardiac remodeling and dysfunction in B 1 Ϫ/Ϫ but not in B 1 ϩ/ϩ . These results may suggest that B 2 receptors play an important role in compensating for lack of B 1 receptors in mice with myocardial infarction. Dual blockade of both B 1 and B 2 eliminates this compensation, leading to further deterioration of cardiac dysfunction and remodeling after myocardial infarction. Key Words: kinins Ⅲ myocardial infarction Ⅲ mice K inins are vasodilator polypeptides released from lowand high-molecular-weight kininogens by plasma and tissue kallikreins and hydrolyzed by angiotensin-converting enzyme (ACE, also called kininase II), neutral endopeptidase-24.11, and other peptidases. 1,2 The biological action of kinins is mediated by activation of at least 2 known Gprotein-coupled receptors, B 1 and B 2 . 3,4 B 2 receptors are constitutively expressed in most tissues, whereas B 1 receptors are weakly expressed under physiological conditions but strongly induced in response to pathological stimuli such as inflammation or tissue injury. 5,6 Recent studies suggest that the B 1 receptor is involved in regulation of vasodilatation, inflammation, and tissue repair, including myocardial infarction. 6 -9 Lamontagne et al 10 reported that activation of the B 1 receptor by intravenous infusion of des-Arg 9 -bradykinin caused a profound hypotensive response, which was partially blocked by the nitric oxide synthase (NOS) inhibitor N Gnitro-L-arginine, suggesting an NO-mediated mechanism. Su et al showed that intracoronary infusion of des-Arg 9 -bradykinin produced dose-dependent coronary vasodilatation, as evidenced by increased coronary diameter and blood flow; this was not affected by a B 2 kinin receptor antagonist (B 2 -ant) but was attenuated by NOS blockade. 5 Activa...

Clinical studies have shown that patients with early Type 2 diabetes often have elevated serum glucagon rather than insulin deficiency. Imbalance of insulin and glucagon in favouring the latter may contribute to impaired glucose tolerance, persistent hyperglycaemia, microalbuminuria and glomerular injury. In the present study, we tested the hypothesis that long-term glucagon infusion induces early metabolic and renal phenotypes of Type 2 diabetes in mice by activating glucagon receptors. Five groups of adult male C57BL/6J mice were treated with vehicle, glucagon alone (1 μg/h via an osmotic minipump, intraperitoneally), glucagon plus the glucagon receptor antagonist [Des-His 1 -Glu 9 ]glucagon (5 μg/h via an osmotic minipump), [Des-His 1 -Glu 9 ]glucagon alone or a high glucose load alone (2 % glucose in the drinking water) for 4 weeks. Glucagon infusion increased serum glucagon by 129 % (P < 0.05), raised systolic BP (blood pressure) by 21 mmHg (P < 0.01), elevated fasting blood glucose by 42 % (P < 0.01), impaired glucose tolerance (P < 0.01), increased the kidney weight/body weight ratio (P < 0.05) and 24 h urinary albumin excretion by 108 % (P < 0.01) and induced glomerular mesangial expansion and extracellular matrix deposition. These responses were associated with marked increases in phosphorylated ERK1/2 (extracellular-signalregulated kinase 1/2) and Akt signalling proteins in the liver and kidney (P < 0.01). Serum insulin did not increase proportionally. Concurrent administration of [Des-His 1 -Glu 9 ]glucagon with glucagon significantly attenuated glucagon-increased BP, fasting blood glucose, kidney weight/body weight ratio and 24 h urinary albumin excretion. [Des-His 1 -Glu 9 ]glucagon also improved glucagoninpaired glucose tolerance, increased serum insulin by 56 % (P < 0.05) and attenuated glomerular injury. However, [Des-His 1 -Glu 9 ]glucagon or high glucose administration alone did not elevate fasting blood glucose levels, impair glucose tolerance or induce renal injury. These results demonstrate for the first time that long-term hyperglucagonaemia in mice induces early metabolic and renal phenotypes of Type 2 diabetes by activating glucagon receptors. This supports the idea that glucagon receptor blockade may be beneficial in treating insulin resistance and Type 2 diabetic renal complications.

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BackgroundAcute kidney injury (AKI) is a complication of coronavirus disease 2019 (COVID-19) that is associated with high mortality. Despite documented kidney tropism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there are no consistent reports of viral detection in urine or correlation with AKI or COVID-19 severity. Here we hypothesize that quantification of SARS-CoV-2 viral load in urine sediment from COVID-19 patients correlates with occurrence of AKI and mortality. MethodsSARS-CoV-2 viral load in urine sediments (U-viral load) was quantified by qRT-PCR in 52 patients with PCR-confirmed COVID-19 diagnosis, hospitalized between March 15th and June 8th, 2020. Immunolabeling of SARS-CoV-2 proteins Spike and Nucleocapsid was performed in two COVID-19 kidney biopsies and urine sediments. Viral infectivity assays were performed from 32 urine sediments. ResultsTwenty COVID-19 patients (39%) had detectable SARS-CoV-2 U-viral load, of which 17 (85%) developed AKI with an average U-viral load 4-times higher than non-AKI COVID-19 patients. U-viral load was highest (7.7-fold) within two weeks after AKI diagnosis. A higher U-viral load correlated with mortality but not with albuminuria or AKI stage. SARS-CoV-2 proteins partially colocalized with the viral receptor ACE2 in kidney biopsies in tubules and parietal cells, and in urine sediment cells. Infective SARS-CoV-2 was not detected in urine sediments. ConclusionOur results further support SARS-CoV-2 kidney tropism. A higher SARS-CoV-2 viral load in urine sediments from COVID-19 patients correlated with increased incidence of AKI and mortality. Urinary viral detection could inform medical care of COVID-19 patients with kidney injury to improve prognosis.