RNA Interference Targeting Liver Angiopoietin-Like Protein 3 Protects from Nephrotic Syndrome in a Rat Model Via Amelioration of Pathologic Hypertriglyceridemia.

Nephrotic syndrome (NS) is associated with metabolic perturbances including profound dyslipidemia characterized by hypercholesterolemia and hypertriglyceridemia. A major underlying mechanism of hypertriglyceridemia in NS is lipoprotein lipase (LPL) deficiency and dysfunction. There is emerging evidence that elevated angiopoietin-like protein 3 (ANGPTL3), an LPL inhibitor that is primarily expressed and secreted by hepatocytes, may be in part responsible for these findings. Furthermore, there is evidence pointing to the contribution of ANGPTL3 to the pathogenesis of proteinuria in NS. Therefore, we hypothesized that inhibition of hepatic ANGPTL3 by RNA interference will ameliorate dyslipidemia and other symptoms of NS and pave the way for a new therapeutic strategy. To this end, we used a subcutaneously delivered, GalNAc (N-Acetylgalactosamine)-conjugated small interfering RNA (siRNA) to selectively target and suppress liver Angptl3 in rats with puromycin-induced NS, which exhibits clinical features of NS including proteinuria, hypoalbuminemia, hyperlipidemia, and renal histologic abnormalities. The study demonstrated that siRNA-mediated knockdown of the liver Angptl3 relieved its inhibitory effect on LPL and significantly reduced hypertriglyceridemia in nephrotic rats. This was accompanied by diminished proteinuria and hypoalbuminemia, which are the hallmarks of NS, and significant attenuation of renal tissue inflammation and oxidative stress. Taken together, this study confirmed the hypothesis that suppression of Angptl3 is protective in NS and points to the possibility that the use of RNA interference to suppress hepatic Angptl3 can serve as a novel therapeutic strategy for NS. SIGNIFICANCE STATEMENT: The current standard of care for mitigating nephrotic dyslipidemia in nephrotic syndrome is statins therapy. However, the efficacy of statins and its safety in the context of impaired kidney function is not well established. Here, we present an alternate therapeutic approach by using siRNA targeting Angptl3 expressed in hepatocytes. As the liver is the major source of circulating Angptl3, siRNA treatment reduced the profound hypertriglyceridemia in a rat model of nephrotic syndrome and was also effective in improving kidney and cardiac function.

Optimal freeze cycle length for renal cryotherapy.

PURPOSE: To our knowledge the optimal freeze cycle length in renal cryotherapy is unknown. Ten-minute time based freeze cycles were compared to temperature based freeze cycles to -20C. MATERIALS AND METHODS: Laparoscopic renal cryotherapy was performed on 16 swine. Time based trials consisted of a double 10-minute freeze separated by a 5-minute thaw. Temperature based trials were double cycles of 1, 5 or 10-minute freeze initiated after 1 of 4 sensors indicated -20C. A 5-minute active thaw was used between freeze cycles. Control trials consisted of cryoneedle placement for 25 minutes without freeze or thaw. Viability staining and histological analysis were done. RESULTS: There was no difference in cellular necrosis between any of the temperature based freeze cycles (p = 0.1). Time based freeze cycles showed more nuclear pyknosis, indicative of necrosis, than the 3 experimental freeze cycles for the renal cortex (p = 0.05) but not for the renal medulla (p = 0.61). Mean time to -20C for freeze cycle 1 was 19 minutes 10 seconds (range 9 to 46 minutes). In 4 of 21 trials (19%) -20C was never attained despite freezing for 25 to 63 minutes. CONCLUSIONS: There was no difference in immediate cellular necrosis among double 1, 5 or 10-minute freeze cycles. Cellular necrosis was evident on histological analysis for trials in which -20C was attained and in freeze cycles based on time alone. With a standard 10-minute cryoablation period most treated parenchyma 1 cm from the probe never attained -20C. Cell death appeared to occur at temperatures warmer than -20C during renal cryotherapy.

Increased Renal 2-Arachidonoylglycerol Level Is Associated with Improved Renal Function in a Mouse Model of Acute Kidney Injury.

Background: Acute kidney injury (AKI) is associated with a significantly increased risk of morbidity and mortality. Ischemia-reperfusion injury (IRI) is a major cause of AKI. In this study, we investigated the role of the endocannabinoid (EC) system in renal IRI using a well-established mouse model. Materials and Methods: Renal ischemia was induced in male C57BL/6 mice by clamping both kidney pedicles for 30 min followed by 24 h of reperfusion. To increase renal 2-arachidonoylglycerol (2-AG) levels, mice were pretreated with JZL184 (16 mg/kg), 30 min before IRI. Serum creatinine and blood urea nitrogen (BUN), renal tubular damage, renal content of ECs and renal expression of markers of inflammation and oxidative stress were measured. Results: Renal IRI was associated with significantly increased serum BUN and creatinine, increased tubular damage score, increased expression of renal markers of inflammation and oxidative stress and elevated renal 2-AG content. Pretreatment with JZL184 was associated with a significant increase in renal 2-AG content and there was also improved serum BUN, creatinine and tubular damage score. However, renal expression of inflammation and oxidative stress markers remained unchanged. Conclusions: This is the first report documenting that renal IRI is associated with an increase in kidney 2-AG content. Further enhancement of 2-AG levels using JZL184 improved indices of renal function and histology, but did not lower renal expression of markers of inflammation and oxidative stress. Further studies are needed to determine the mechanisms responsible for the effects observed and the potential value of 2-AG as a therapeutic target in renal IRI.

Isolated amygdala neurocysticercosis in a patient presenting with déjà vu and olfactory auras. Case report.

Neurocysticercosis is the most common parasitic infection in the CNS and a leading cause of epilepsy. Since it is a circumscribed lesional cause of epilepsy, specific locations of neurocysticercal lesions may lead to specific clinical presentations. The authors describe a 17-year-old Hispanic boy who had a single enhancing bilobar mass in the right amygdala. Initially, the patient presented with secondarily generalized tonic-clonic seizures, which resolved with antiepilepsy drug therapy. On further investigation, he was found to have persistent olfactory and déjà vu auras. A right amygdalectomy without hippocampectomy was performed, and both the seizures and auras immediately resolved. Pathological analysis revealed neurocysticercosis. To the authors' knowledge, this case is the first reported instance of 2 distinct mesial temporal aura semiologies associated with localized neurocysticercosis in the amygdala and successfully treated with resection. Uniquely, the case demonstrates that both olfactory and déjà vu auras can emanate from the amygdala.