Renal parenchymal hypoxia, hypoxia response and the progression of chronic kidney disease

Renal parenchymal hypoxia, documented under a variety of clinical conditions, conceivably contributes to the progression chronic kidney disease. In this review, normal physiologic medullary hypoxia and abnormal profiles of renal pO(2) in chronic kidney diseases are presented, and the mechanisms leading to anomalous renal tissue oxygenation are discussed. Direct measurements of pO(2) with oxygen electrodes, immunostaining with pimonidazole (which binds to regions with very low pO(2)), or the detection of hypoxia-inducible factor (HIF)-alpha (which accumulates in hypoxic regions, initiating hypoxia-adaptive responses), all serve to detect the distribution and extent of renal parenchymal hypoxia under experimental settings. The use of BOLD MRI as a noninvasive tool, detecting deoxygenated hemoglobin in hypoxic renal tissues, has evolved from experimental settings to human studies. All these modalities indicate that abnormal renal oxygenation develops under conditions such as chronic glomerular, tubulointerstitial or renovascular disease, in diabetes, hypertension, aging, renal hypertrophy, anemia or obstructive uropathy. Abnormal renal tissue hypoxia modifies the pattern of regional gene expression, evoking a host of adaptive and renoprotective pathways (such as HIF-mediated erythropoietin or heme-oxygenase-1), in parallel with the induction of potentially harmful mediators that participate in the progression of chronic kidney injury. Slowing the progression of chronic kidney disease may be achieved by a better understanding of these parallel processes and the accomplishment of a selective control of such protective and maladaptive responses.     

Severe hypoglycemia from clarithromycin-repaglinide drug interaction

Many drugs have been reported to interact with repaglinide in patients with type 2 diabetes mellitus, resulting in hypoglycemia. However, to our knowledge, an interaction between clarithromycin and repaglinide in these patients has not been previously reported. We describe an 80-year-old man with end-stage renal disease and well-controlled type 2 diabetes (hemoglobin A1c < 7%) who was hospitalized for treatment of severe hypoglycemia. He had been receiving repaglinide 0.5 mg 3 times/day for the previous 2 years. Clarithromycin 500 mg twice/day had been started for Helicobacter pylori infection several days before admission. Within 48 hours of starting the drug, he developed severe hypoglycemia, which resolved with intravenous glucose administration. However, 48 hours later, the patient again experienced hypoglycemia and was unresponsive. Intravenous glucose administration again resolved the problem. Repaglinide was discontinued, and no further hypoglycemic episodes occurred. Clinicians should be aware of this possible clarithromycin-repaglinide interaction; in particular, in elderly patients with type 2 diabetes who are taking repaglinide and begin clarithromycin therapy, blood glucose levels should be monitored closely for potential dosage adjustment of repaglinide.     

Ex vivo endothelin dependent contraction of the remodeled rat spiral artery

Introduction

Similarities of the rat to the human placenta make rat pregnancy models relevant to the study of human gestational diseases. Understanding of species differences is necessary to extrapolate from animal models to humans. We observed alpha-smooth muscle actin (αSMA) expression in rat endovascular trophoblasts (EVasT) and investigated the spatial and temporal expression of smooth muscle (SM) proteins and their potential function in remodeled spiral artery.

Methods

Rat placentas were examined from gestational day 13 to term, and were immunostained for cytokeratin, αSMA, alpha heavy chain of SM myosin, non-muscle myosin, Rho proteins, regulators of SM gene expression, myocardin, an early marker of SM differentiation and endothelin receptors A and B (ETA, ETB). Transmission electron microscopy (TEM) was performed. Modified spiral artery rings were studied ex vivo for endothelin-1- induced contraction.

Results

EVasT expressed SM proteins co-localizing with cytokeratin confirming their trophoblastic origin from gestational day 13 to term. Thin fibers, consistent with actin fibers, were observed by TEM, in the cellular localization of αSMA in EVasT.Functional experiments revealed that addition of 10⁻⁷ M endothelin-1 ex vivo reduced vascular lumen area by 11.1% ± 1.8% compared with control. This effect was reduced to only 1.0 ± 1.7% with ETA antagonist, and to 5.4 ± 1.7% contraction by ETB antagonist, p < 0.002, for all.

Discussion

The expression of SM proteins in EVasT along with the contractibility of the rat remodeled spiral artery ex vivo, suggest that some vascular tone is potentially maintained by endothelin-1, and may play a role in situations of dysregulation of the vasoactive systems.     

Intrauterine Growth Restriction and Shallower Implantation Site in Rats with Maternal Hyperinsulinemia are Associated with Altered NOS Expression

Nitric oxide synthase (NOS) plays an important role in hypertensive disorders of pregnancy. In the context of the known association between hyperinsulinemia and hypertension, we studied the expression of the 3 isoforms of NOS (neuronal-nNOS, inducible-iNOS, and endothelial-eNOS) in the placenta and implantation site of our insulin-induced intrauterine growth restriction (IUGR) rat model in which the normal gestational blood pressure decline is abrogated.The fetuses of hyperinsulinemic dams were significantly smaller than those of normal pregnant dams (male fetal weight = 4.8 ± 0.5 g vs. 5.4 ± 0.4 g, hyperinsulinemic vs. control, respectively; female fetal weight = 4.5 ± 0.5 g vs. 5.1 ± 0.4 g, hyperinsulinemic vs control, respectively, p < 0.0001). Their placentas weighed less than those of normal pregnant dams (0.44 ± 0.08 g in hyperinsulinemic dams vs. 0.50 ± 0.09 g, p < 0.0001) and their implantation site, designated the mesometrial triangle, was also smaller. Endovascular trophoblasts were found more often and in greater depth in normal pregnant dams. Possibly as a compensatory mechanism, the endovascular trophoblasts formed cell groups rather than a monolayer and occupied a larger portion of the arterial perimeter in arteries of hyperinsulinemic dams.iNOS expression increased by 80% (p < 0.0001) and 180% (p = 0.045) in placenta and mesometrial triangle of hyperinsulinemic dams, respectively. The expression of eNOS was reduced by 17% (p = 0.048) in the placenta and did not change significantly in the mesometrial triangle (p > 0.05). nNOS expression was decreased by 37% (p = 0.03) in the placenta and increased by 53% (p = 0.035) in the mesometrial triangle of hyperinsulinemic dams. Immunohistochemistry revealed prominent expression of iNOS in the placental junctional zone and in interstitial and endovascular trophoblasts in the mesometrial triangle. Assuming a role in trophoblastic invasion, the increased expression of iNOS in hyperinsulinemic dams explains the “compensatory” pattern of trophoblastic invasion. Expression of eNOS was prominent in endothelial cells and weak in endovascular trophoblasts.In our model of gestational hyperinsulinemia-induced IUGR, we found not only differing expression of the 3 NOS isoforms in the cellular elements of the placenta and mesometrial triangle, but also divergent modes of altered NOS isoform expression. These findings suggest, in accordance with other publications, that each isoform may have a distinct function in the placenta and placental bed. The differing expression of the 3 NOS isoforms in the placenta and in the mesometrial triangle in rat IUGR seems to result from the hyperinsulinemia and the resulting IUGR phenotype.