Insulin Resistance, Obesity, Hypertension, and Renal Sodium Transport

Sodium transport through various nephron segments is quite important in regulating sodium reabsorption and blood pressure. Among several regulators of this process, insulin acts on almost all the nephron segments and is a strong enhancer of sodium reabsorption. Sodium-proton exchanger type 3 (NHE3) is a main regulator of sodium reabsorption in the luminal side of proximal tubule. In the basolateral side of the proximal tubule, sodium-bicarbonate cotransporter (NBCe1) mediates sodium and bicarbonate exit from tubular cells. In the distal nephron and the connecting tubule, epithelial sodium channel (ENaC) is of great importance to sodium reabsorption. NHE3, NBCe1, and ENaC are all regulated by insulin. Recently with-no-lysine (WNK) kinases, responsible for familial hypertension, stimulating sodium reabsorption in the distal nephron, have been found to be also regulated by insulin. We will discuss the regulation of renal sodium transport by insulin and its roles in the pathogenesis of hypertension in insulin resistance

Roles of Renal Proximal Tubule Transport in Acid/Base Balance and Blood Pressure Regulation

Sodium-coupled bicarbonate absorption from renal proximal tubules (PTs) plays a pivotal role in the maintenance of systemic acid/base balance. Indeed, mutations in the Na+-HCO3- cotransporter NBCe1, which mediates a majority of bicarbonate exit from PTs, cause severe proximal renal tubular acidosis associated with ocular and other extrarenal abnormalities. Sodium transport in PTs also plays an important role in the regulation of blood pressure. For example, PT transport stimulation by insulin may be involved in the pathogenesis of hypertension associated with insulin resistance. Type 1 angiotensin (Ang) II receptors in PT are critical for blood pressure homeostasis. Paradoxically, the effects of Ang II on PT transport are known to be biphasic. Unlike in other species, however, Ang II is recently shown to dose-dependently stimulate human PT transport via nitric oxide/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension. In this paper, we will review the physiological and pathophysiological roles of PT transport

Carbon ion radiotherapy for oligo-recurrent lung metastases from colorectal cancer: a feasibility study.

BackgroundThe purpose of this study was to evaluate the efficacy and feasibility of carbon ion radiotherapy (CIRT) for oligo-recurrent lung tumors from colorectal cancer (CRC). \nMethodsFrom May 1997 to October 2012, 34 consecutive patients with oligo-recurrent pulmonary metastases from CRC were treated with CIRT. The patients were not surgical candidates for medical reasons or patient refusal. Using a respiratory-gated technique, carbon ion therapy was delivered with curative intent using 4 coplanar beam angles. A median dose of 60 GyE (range, 44–64.8 GyE) was delivered to the planning target volume (PTV), with a median daily dose of 15 GyE (range, 3.6–44 GyE). Treatment outcome was analyzed in terms of local control rate (LCR), survival rate, and treatment-related complications. \nResultsIn total, 34 patients with 44 oligo-recurrent pulmonary lesions were treated with CIRT. Median follow-up period was 23.7 months. The 2- and 3-year actuarial LCRs of the treated patients were 85.4% ± 6.2% and 85.4% ± 6.2%, respectively. Overall survival was 65.1% ± 9.5% at 2 years, and 50.1% ± 10.5% at 3 years. Although survival rates were relatively worse in the subsets of patients aged < 63 years or with early metastasis (< 36 months after resection of primary site), these factors were not significantly correlated with overall survival (P = 0.13 and 0.19, respectively). All treatment-related complications were self-limited, without any grade 3–5 toxicity. \nConclusionsCIRT is one of the most effective nonsurgical treatments for colorectal lung metastases, which are relatively resistant to stereotactic body radiotherapy. CIRT is considered to be the least invasive approach even in patients who have undergone repeated prior thoracic metastasectomies

Roles of ERK and cPLA2 in the Angiotensin II-Mediated Biphasic Regulation of Na+-HCO3− Transport

Regulation of renal proximal transport by angiotensin II (Ang II) is biphasic: low concentrations (picomolar to nanomolar) stimulate reabsorption, but higher concentrations (nanomolar to micromolar) inhibit reabsorption. Traditionally, the stimulatory effect has been attributed to activation of protein kinase C and/or a decrease in intracellular cAMP, whereas the inhibitory action has been attributed to the activation of phospholipase A2 (PLA2) and the subsequent release of arachidonic acid. The Ang II receptor subtype responsible for these effects and the intracellular signaling pathways involved are not completely understood. We isolated proximal tubules from wild-type, Ang II type 1A receptor (AT1A)–deficient, and group IVA cytosolic phospholipase A2 (cPLA2α)–deficient mice, and compared their responses to Ang II. In wild-type mice, we found that the stimulatory and inhibitory effects of Ang II on Na+-HCO3− cotransporter activity are both AT1-mediated but that ERK activation only plays a role in the former. The stimulatory effect of Ang II was also observed in AT1A-deficient mice, suggesting that this occurs through AT1B. In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA2α activation because high-concentration Ang II stimulated Na+-HCO3− cotransporter activity when cPLA2α activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA2α/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA2α in a concentration-dependent manner via AT1, and that the balance between ERK and cPLA2α activities determines the ultimate response to Ang II in intact proximal tubules

Arachidonic Acid Metabolites Inhibit the Stimulatory Effect of Angiotensin II in Renal Proximal Tubules

Angiotensin II (Ang II) regulates renal proximal transport In a biphasic way via Ang II type I receptor (AT(1)). Whereas extracellular signal-regulated kinase (ERK) activation mediates the stimulatory effect, cytosolic phospholipase A(2) (cPLA(2)) mediates the Inhibitory effect Independently of ERK. In this study, we tested the hypothesis that the cPLA(2)/P450 epoxygenese pathway might work to suppress the Ang II-mediated ERK activation. In the presence of arachidonic acid or 5,6-epoxyeicosatrienoic acid (EET), Ang II failed to stimulate the Na-HCO(3) cotransporter activity In renal proximal tubules isolated from wild-type, AT(1A)-deficient, and cPLA2-alpha-deficient mice. In addition, Ang II failed to induce a significant ERK phosphorylation In the presence of arachidonic acid or 5,6-EET. Arachidonic acid or 5,6-EET also suppressed the stimulatory effect of Ang II on net proximal tubule bicarbonate absorption without changing cell Call concentrations. These results indicate that the cPLA(2)-alpha/P450/EET pathway blocks the stimulatory effect of Ang II by suppressing the ERK activation. Thus, the cPLA2-a/P450/EET pathway may operate as a unique negative feedback mechanism to attenuate excessive Ang II activity in the renal proximal tubules, where extremely high concentrations of Ang II are found. (Hypertens Res 2008; 31: 2155-2164)Peripheral Vascular DiseaseSCI(E)1ARTICLE122155-21643

Survival comparison between radical surgery and definitive chemoradiation in 267 esophageal squamous cell carcinomas in a single institution: A propensity-matched study

<div><p>Objective</p><p>To compare radical surgery with definitive chemoradiation (CRT) for esophageal squamous cell carcinoma using propensity score (PS) matching at our single institution.</p><p>Materials and methods</p><p>A total of 386 consecutive, surgically treated and 243 CRT-treated cases between 2001 and 2014 were analyzed. PS was calculated using multivariable analysis (logistic regression) for pairs of variables such as treatment time, age, sex, primary tumor location, clinical stage, and clinical T- and N-stage for patients after excluding clinical T4 and M1 cases. According to PS, 133 surgically-treated and 134 CRT-treated cases were selected randomly by software.</p><p>Results</p><p>The patients’ median age was 68 years in the CRT group and 71 years in the surgery group. Clinical stage II-III, T3, N0 (according to the 7th American Joint Committee on Cancer-2009), and upper plus middle thoracic esophageal disease were seen in 68%, 44%, 54%, and 59%, respectively, in the CRT group and 64%, 47%, 55%, and 64%, respectively, in the surgery group. The 3- and 5-year overall survival was 47.1% and 34.0% in the CRT group and 68.3% and 54.4% in the surgery group (<i>p</i> = 0.0019). The 3- and 5-year progression-free survival was 45.3% and 38.8% in the CRT group and 61.1% and 54.4% in the surgery group (<i>p</i> = 0.022).</p><p>Conclusion</p><p>CRT may be inferior to surgery in survival, although a selection bias for patients selected for a non-operative approach cannot be excluded, especially since surgery is the standard of care at this institution. A prospective randomized clinical trial will be necessary to draw a definite conclusion.</p></div

Consort diagram of the study.

<p>Consort diagram of the study.</p