Mechanism of the decreased eicosanoid production in vitro in response to angiotensin II in glomeruli of rats with bilateral ureteral obstruction

Summary: Glomeruli isolated from rats with bilateral ureteral obstruction (BUO) of 24 h duration synthesized significantly greater amounts of prostaglandin (PG)E₂, 6-keto PGF_1a, thromboxane (Tx)B₂ and leukotriene (LT)B₄ than glomeruli isolated from sham-operated control (SOC) rats. Glomeruli isolated from SOC rats produced increased amounts of these four eicosanoids compared to basal conditions when 100 nmol/L angiotensin II (AII) was added in vitro to the preparations. However, no significant increases in glomerular eicosanoid production were seen under these conditions in glomeruli of rats with BUO. to examine the mechanims underlying imparied eicosanoid production in glomeruli of rats with BUO exposed to AII in vitro, we measured the activities of phosphatidylethanolamine (PE)-specific phospholipase A₂ (PLA₂), 5-lipoxygenase and the cyclo-oxygenase pathway enzymes including cyclo-oxygenase, PGE₂ isomerase and PGI₂ and Tx synthases under basal conditions and after addition of 100 nmol/L AII in vitro in glomeruli isolated from SOC rats and rats with BUO of 24 h duration. the basal activities of all of these enzymes were significantly greater in glomeruli of rats with BUO compared to SOC rats. In glomeruli of SOC rats, the activities of these enzymes were markedly increased when exposed to 100 nmol/L AII in vitro compared to basal conditions. By contrast, no significant changes in the activities of enzymes involved in eicosanoid formation above baseline were seen in glomeruli of rats with BUO exposed to AII in vitro. the production rates of eicosanoids paralleled the activities of these enzymes under basal and AII-stimulated conditions in glomeruli obtained from SOC rats and rats with BUO. Thus, the lack of increased levels of PGE₂, 6-keto PGF_1a, TxB₂ and LTB₄, when glomeruli of rats with BUO of 24 h duration are exposed to 100 nmol/L AII in vitro, maybe due mainly to either the action of PE-specific PLA₂ or the combined action of PE-specific PLA₂, cyclo-oxygenase pathway enzymes and 5-lipoxygenase set at, or near, maximum levels as a consequence of BUO.     

Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.     

G-protein stimulation inhibits amiloride-sensitive Na/H exchange independently of cyclic AMP.

G-proteins are heterotrimeric proteins involved in many transmembrane signaling events. Both the renal basolateral membrane and the renal brush border membrane contain large quantities of these proteins. G-proteins appear related to hormonal signaling in the basolateral membrane and presumably affect ion gating in the brush border. We investigated the influence of G-proteins on the amiloride-sensitive Na/H exchanger, the activity of which is regulated at least in part by cAMP-dependent protein kinase, by measuring the amiloride-sensitive component of [22Na+] uptake in rat renal brush border membrane vesicles (BBMV) in the presence of a pH gradient. Incubation of vesicles with AlF4- (10 microM Al3+, 10 mM F-) resulted in significant inhibition of amiloride-sensitive [22Na+] uptake at both 20 seconds and 5 minutes of incubation. Incorporation of GTP gamma S into BBMV by transient hypotonic lysis also resulted in significantly reduced amiloride-sensitive [22Na+] uptake compared to controls at both time points. This inhibition could be reversed by GDP beta S. Similar lysis in the presence of 10 microM GDP beta S alone had no significant effect. When Na(+)-dependent [14C]-D-glucose uptake into BBMV was studied no significant effect of these G-protein modulating agents was observed. Adenylate cyclase activity could not be stimulated in these BBMV preparations using standard techniques. Furthermore, cAMP-dependent protein kinase activity, strongly stimulated in these BBMV by exogenously added cAMP, was not stimulated by 10 microM GTP gamma S alone. These findings suggest that the amiloride-sensitive Na/H exchanger can be regulated by G-proteins independently of adenylate cyclase and cAMP-dependent protein kinase.     

Consequences of the persistence of large thyroid remnants after bilateral thyroidectomy for differentiated thyroid cancer

Twenty-three patients submitted to thyroidectomy and before ablative therapy and with cervical uptake >10% were compared to 48 patients with uptake <2%. All but 3 patients with large remnants reached TSH levels >30 mIU/l after thyroxin withdrawal. Cervical pain requiring anti-inflammatory treatment after radioiodine was more frequent in patients with larger remnants (34.7% vs. 10.4%). Remnant ablation was successful in 56% of the individuals with uptake >10% and in 93.3% of those with uptake <2%. The sensitivity of diagnostic scanning for pulmonary metastases was similar (71.4% vs. 77.7%). The specificity of stimulated thyroglobulin at a cut-off of 5 ng/ml was 100% for patients with discrete remnants but only 37.5% for the others. We conclude that significant thyroid remnants (cervical uptake >10%) result in a lower efficacy of ablation, cause more local symptoms after radioiodine, and compromise the specificity of thyroglobulin measurements.     

Correlation between cervical uptake and results of postsurgical radioiodine ablation in patients with thyroid carcinoma

OBJECTIVE: The objective of this study was to determine the relationship between cervical uptake after thyroidectomy and the success of treatment of cervical remnants with high-dose radioiodine (100 mCi). METHODS: Cervical uptake was retrospectively analyzed after total thyroidectomy and before treatment with radioactive iodine in 142 patients seen at our service who received 100 mCi iodine-131 and whose posttreatment scan only showed cervical uptake without distant metastases. The patients were divided into 5 groups according to the uptake result obtained before ablative therapy. RESULTS: Successful treatment, defined as stimulated thyroglobulin levels <5 ng/mL and a clean scan or only discrete cervical uptake (0.5%) 6 months to 1 year after surgery, was obtained as follows: patients with uptake <1% (n = 48) showed 95.8% treatment efficacy, those with uptake of 1-2% (n = 32) 94% efficacy, and those with uptake of 2-5% (n = 30) reached 83% success, whereas patients with uptake of 5-10% (n = 20) presented 70% efficacy, and treatment was successful in only 50% of patients with uptake >10% (n = 12). CONCLUSIONS: Postoperative measurement of cervical I-131 uptake could be a reasonable predictor of the success of the remnant ablation, and perhaps a guide in deciding the ablative dose of I-131, based on the inverse correlation between the uptake and ablation efficacy.