Yoon-Kyung Chang

Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

Sildenafil is the first commercially available selective inhibitor of phosphodiesterase-5 (PDE5) and is widely used for the treatment of erectile dysfunction. In recent years, investigations of the role of sildenafil in cardioprotection in animal models have received considerable interest. We evaluated whether sildenafil can attenuate cisplatin-induced nephrotoxicity in a rat experimental model. Male Sprague-Dawley rats were divided into five groups: control rats, sildenafil-control rats, cisplatin-injected rats (5 mg kg(-1) IP, single dose), sildenafil-treated cisplatin-injected rats (0.4 mg kg(-1), daily), and sildenafil+NG-nitro-l-arginine methyl ester hydrochloride (l-NAME)-treated rats. The molecular, functional, and structural parameters of the kidney were measured. At 96 h after cisplatin injection, serum levels of creatinine were lower in rats treated with both sildenafil+cisplatin compared with rats treated with cisplatin alone, and renal iNOS and eNOS expression was significantly higher in sildenafil+cisplatin-treated rats compared with rats treated with cisplatin alone (all P<0.05). Renal Bax gene and protein expression was significantly higher in cisplatin-treated rats compared with control rats, and sildenafil treatment significantly reduced the levels of Bax and increased the renal Bax/Bcl-2 ratio (P<0.05). Sildenafil treatment also reduced renal caspase-3 activation and TUNEL-positive apoptotic cells. These data suggest that sildenafil attenuates experimental cisplatin-induced nephrotoxicity by preventing apoptosis.

Erythropoietin Attenuates Renal Injury in an Experimental Model of Rat Unilateral Ureteral Obstruction via Anti-Inflammatory and Anti-Apoptotic Effects

PURPOSE Erythropoietin was recently shown to exert important cytoprotective and anti-apoptotic effects in injury models of the brain, heart and kidney. We examined whether erythropoietin also attenuates renal injury in a rat model of unilateral ureteral obstruction via anti-apoptotic and anti-inflammatory actions. MATERIALS AND METHODS We divided Sprague-Dawley rats (Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea) into 4 groups, including 1-vehicle treated with sham operation, 2-vehicle treated with unilateral ureteral obstruction for 3 days, 3-erythropoietin treatment with sham operation and 4-erythropoietin treatment for unilateral ureteral obstruction for 3 days. The erythropoietin treatment dose was 3,000 IU/kg per day intraperitoneally, administered daily. We compared competitive reverse transcriptase-polymerase chain reaction data on transforming growth factor-beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, osteopontin, Fas and Bcl-2. Furthermore, we examined Western blots for caspase-3 and light microscopy findings with hematoxylin and eosin staining. We applied immunohistochemistry for transforming growth factor-beta, ED-1 and caspase-3, and TUNEL in each group. RESULTS Transforming growth factor-beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, osteopontin and Fas mRNA levels in the erythropoietin treated, unilateral ureteral obstruction group were significantly lower than in the obstruction only group. The Bcl-2 mRNA level in the erythropoietin treated obstruction group was significantly higher than in the obstruction only group. Caspase-3 activity in the erythropoietin treated obstruction group was significantly lower than in the obstruction only group. On light microscopy interstitially infiltrated inflammatory cells were significantly decreased in the erythropoietin treated obstruction group compared to the obstruction only group. On immunohistochemistry the erythropoietin treated obstruction group showed significantly fewer reactions for transforming growth factor-beta, ED-1 and caspase-3 compared to the obstruction only group. Erythropoietin treatment in rats with unilateral ureteral obstruction significantly decreased the number of TUNEL positive cells. CONCLUSIONS Erythropoietin exerts renoprotective effects in an experimental unilateral ureteral obstruction rat model via anti-apoptotic and anti-inflammatory actions.

Effects of neutral pH and low-glucose degradation product-containing peritoneal dialysis fluid on systemic markers of inflammation and endothelial dysfunction: a randomized controlled 1-year follow-up study

BACKGROUND The local peritoneal effects of low-glucose degradation product (GDP)-containing peritoneal dialysis fluid (PDF) have been extensively described. However, the systemic effects of prolonged prescription of these solutions are unknown. This study aimed to evaluate the effects of neutral pH and low-GDP PDF on systemic inflammation and endothelial dysfunction markers in peritoneal dialysis (PD) patients. METHODS This is a multicenter, open labeled, randomized controlled trial including one hundred fifty-two patients initiating continuous ambulatory peritoneal dialysis for end-stage renal disease from seven centers in Korea. Participants were randomly allocated to conventional PDF (Stay safe®; Fresenius Medical Care, Bad Homburg, Germany) or low-GDP PDF (Balance®; Fresenius Medical Care) and were followed for 1 year. Primary outcome variable was the inflammation and endothelial dysfunction index (IEDI), a composite score derived from serum levels of soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cellular adhesion molecule (sVCAM)-1 and high-sensitivity C-reactive protein (hs-CRP). sICAM-1, sVCAM-1, residual renal function (RRF), peritoneal membrane transport characteristics, ultrafiltration volume and nutritional parameters were measured as secondary outcome variables. RESULTS Of 152 patients randomized, 146 (low-GDP: conventional PDF, 79:67) patients entered the trial (46% male, 53% with diabetes mellitus). At 12-month follow-up, the low-GDP group had significantly lower levels of IEDI, sICAM-1 and sVCAM-1 compared to the conventional group; hs-CRP was not different between groups. Peritoneal transport characteristics, RRF, nutritional parameters, incidence of peritonitis and death-censored technique survival were not different between groups. CONCLUSION Neutral pH and low-GDP PDF likely produce fewer changes in markers of endothelial dysfunction compared to conventional PDF in incident PD patients.

C-phycocyanin attenuates cisplatin-induced nephrotoxicity in mice.

Although cisplatin is a highly effective antineoplastic agent, nephrotoxicity is its major clinical problem. Recently, it was reported that Spirulina, a blue-green algae, has potent antioxidant properties. The aim of this study was to establish the possible protective role of C-phycocyanin (PC), one of the active ingredients of Spirulina, against cisplatin-induced nephrotoxicity. This study was carried out using human kidney-2 (HK-2) cells and male C57BL6 mice. Cells and mice were divided into four groups; untreated control group, PC-treated control group, cisplatin-treated group, and PC plus cisplatin-treated group. The molecular, functional, and structural parameters were measured. PC significantly attenuated blood urea nitrogen, serum creatinine, renal histological damages, and apoptotic cell death in cisplatin-treated mice. The cisplatin-induced cell death was significantly attenuated in cells pretreated with PC. PC also significantly attenuated the elevation of p-ERK, p-JNK, and p-p38 induced by cisplatin treatment. The expression of Bax, caspase-9, and caspase-3 in cisplatin-treated cells were also decreased by PC treatment. In conclusion, PC ameliorates cisplatin-induced nephrotoxicity and, at least in part, suppression of p-ERK, p-JNK, p-p38, Bax, caspase-9, and caspase-3 may be involved in this mechanism.

Nephrocalcinosis Associated with Primary Aldosteronism

Chul Woo Yang. MD, Department of internal Medieine, Kang Nam St. Mary’s Hospital, Catholic University Medical College, No. 505 Banpo-Dong Seoeho-Ku, 137-040 (South Korea) Dear Sir, It has been known that prolonged hypo-kalemia is associated with renal interstitial fibrosis, renal cyst formation and impairment of renal function [Tj; however, nephrocalcinosis associated with primary aldosteronism is rarely reported [2]. A 45-year-old woman was admitted to our hospital because of intermittent muscle cramps, polyuria and polydip-sia which developed 7 years earlier. At admission, blood pressure was 200/110 mm Hg. Biochemical findings indicated sodium 146 mEq/1, potassium 2.2 mEq/1, chloride 109 mEq/1, BUN 8.6 mg/dl, creatinine 0.8 mg/dl, total protein 7.8 g/dl, albumin 4.4 g/dl, AST 19 IU/1, ALT 13 IU/1, alkaline phosphatase 113 IU/1, calcium 8.9 mg/dl, phosphorus 2.5 mg/dl, magnesium 2.2 mg/dl. Twenty-four hour urine collections indicated sodium 135 mEq, potassium 50 mEq, calcium 102 mg, phosphorus 168 mg, magnesium 4.2 mg. Arterial blood gas analysis showed pH 7.42. pO: 89.5 mm Hg. HCO, 29.5 mm Hg, PCCK 44.7 mm Hg, and urine gas analysis showed pH 6.87, P02 119.4 mm Hg. PC02 36.6 mm Hg. HCO, 9.2 mm Hg. The hormone study revealed PTH 0.24 ng/ml (normal: -0.88 g/ml). 25-(OH) vitamin D 11.6 ng/ml (normal: 9-42 ng/ml), ACTH 3.0 pg/ml (normal: -37 pg/ml), 24-hour urine cortisol 57.8 μg/day (normal: 10-80 μg/day), metane-phrine 1.0 mg/day (normalup to 1.2 mg/ day), VMA 4.1 mg/day (normal: below 5 mg/ day). Plasma renin activity and aldosterone concentration before and after adrenalec-tomy are shown on table 1. Intravenous pyelography findings were unremarkable. The computed tomography of the abdomen showed bilateral medullary calcification and adrenal mass (2× 1 cm) consistent with adrenal tumor (fig. 1. 2). Adrenalec-tomy was performed on the 9th hospital day, and clinical symptoms, blood pressure and hypokalemia improved shortly after operation. This case shows that prolonged hypokalemia in primary aldosteronism can be one of the causes of nephrocalcinosis. The causes of nephrocalcinosis are primary hyperparathy-

Correction: Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury.

[This corrects the article DOI: 10.1371/journal.pone.0158810.].