Emerging evidence suggests that the intravenous injection of bone marrow-derived stromal cells (BMSC) improves renal function after acute tubular injury, but the mechanism of this effect is controversial. In this article, we confirm that intravenous infusion of male BMSC reduced the severity of cisplatin-induced acute renal failure in adult female mice. This effect was also seen when BMSC (or adipocyte-derived stromal cells (AdSC)), were given by intraperitoneal injection. Infusion of BMSC enhanced tubular cell proliferation after injury and decreased tubular cell apoptosis. Using the Y chromosome as a marker of donor stromal cells, examination of multiple kidney sections at one or four days after cell infusion failed to reveal any examples of stromal cells within the tubules, and only rare examples of stromal cells within the renal interstitium. Furthermore, conditioned media from cultured stromal cells induced migration and proliferation of kidney-derived epithelial cells and significantly diminished cisplatin-induced proximal tubule cell death in vitro. Intraperitoneal administration of this conditioned medium to mice injected with cisplatin diminished tubular cell apoptosis, increased survival, and limited renal injury. Thus, marrow stromal cells protect the kidney from toxic injury by secreting factors that limit apoptosis and enhance proliferation of the endogenous tubular cells, suggesting that transplantation of the cells themselves is not necessary. Identification of the stromal cell-derived protective factors may provide new therapeutic options to explore in humans with acute kidney injury.
1 We examined reserpine-induced chemical denervation supersensitivity with special reference to alpha-1 adrenoceptor (AR) subtypes. 2 Chronic treatment with reserpine for 2 weeks depleted noradrenaline in the tail artery and spleen of rats. Noradrenaline in the thoracic aorta was negligible before and after reserpine treatment. 3 The treatment with reserpine produced supersensitivity in the contractile responses of the rat tail artery to phenylephrine, 5-HT and KCl, resulting in leftward shift of concentration-response curves (11.6-, 2.5-and 1.1-fold at EC 50 value, respectively). These results suggest a predominant sensitization of the alpha-1 AR-mediated response by reserpine treatment. 4 BMY 7378 at a concentration (30 nM) specific for blocking the alpha-1D AR subtype, but not KMD-3213 at a concentration (10 nM) selective for blocking the alpha-1A AR subtype, inhibited the supersensitivity of the phenylephrine-induced response in the reserpine-treated artery. On the other hand, the response to phenylephrine in reserpine-untreated artery was selectively inhibited by the same concentration of KMD-3213, but not by BMY 7378. Prazosin, a subtype-nonselective antagonist, blocked the responses to phenylephrine with the same potency, regardless of reserpine treatment. 5 In the thoracic aorta and spleen, no supersensitivity was produced in the responses to phenylephrine by reserpine treatment. 6 In a tissue segment-binding study using [ 3 H]-prazosin, the total density and affinity of alpha-1 ARs in the rat tail artery were not changed by treatment with reserpine. However, alpha-1D AR with high affinity for BMY 7378 was significantly detected in reserpine-treated tail artery, in contrast to untreated artery. Decreases in alpha-1A AR with high affinity for KMD-3213 and alpha-1B AR with low affinities for KMD-3213 and BMY 7378 were also estimated in reserpine-treated tail artery. 7 Alpha-1D AR mRNA in rat tail artery increased to three-folds by reserpine treatment, whereas the levels of alpha-1A and 1B mRNAs were not significantly changed. 8 The present results suggest that chronic treatment with reserpine affects the expression of alpha-1 AR subtypes of rat tail artery and that the induction of alpha-1D ARs with high affinity for catecholamines is in part associated with reserpine-induced supersensitivity.
Serotonin (5-HT2) antagonists show high affinity for the α1-adrenoceptor (α1-AR) in addition to the 5-HT2 receptor. In the present study we compared the pharmacological characteristics of a new 5-HT2 antagonist sarpogrelate and its active metabolite M-1 with those of ketanserin on human recombinant α1-AR subtypes. In the binding study, sarpogrelate, M-1 and ketanserin produced concentration-dependent inhibition of 3H-prazosin binding to α1-ARs. Among the three drugs, ketanserin showed the highest affinity for α1a-, α1b- and α1d-ARs (pKi 8.0, 8.3 and 7.6, respectively). Sarpogrelate had a relatively low affinity for the three subtypes (6.3 , 6.4 and 6.3, respectively) and M-1 showed medium affinity (7.1, 7.1 and 6.1, respectively). Chinese hamster ovary (CHO) cells expressing each α1-AR subtype showed concentration-dependent inositol phosphate (IP) accumulation in response to phenylephrine. The concentration response curves were shifted to the right by three drugs, and the pKb values were close to the pKi values in the binding study. In addition to these effects, sarpogrelate and M-1, but not ketanserin produced an increase in the basal IP level of α1d-expressed CHO cells, although the increase was less than that of phenylephrine. The present results indicate that sarpogrelate and M-1 have antagonistic activity to the three α1-AR subtypes, but their affinities are significantly lower than those of ketanserin.
We established three human embryonic kidney (HEK) 293 cell lines stably expressing ␣ 1 -adrenoceptor (AR) subtypes, one (␣ 1A
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