N-methyl-d-aspartate receptor hyperfunction contributes to d-serine-mediated renal insufficiency.

Glutamate N-methyl-d-aspartate receptor (NMDAR) hyperfunction is known to contribute to acute renal failure due to ischemia-reperfusion and endotoxemia. d-Serine is a coagonist for NMDAR activation, but whether NMDARs play a role in d-serine-mediated nephrotoxicity remains unclear. Here, we demonstrate that NMDAR blockade ameliorated d-serine-induced renal injury. In NMDAR-expressing LLC-PK1 cells, which were used as a proximal tubule model, d-serine but not l-serine induced cytotoxicity in a dose-dependent manner, which was abrogated by the selective NMDAR blockers MK-801 and AP-5. Time-dependent oxidative stress, evidenced by gradually increased superoxide and H2O2 production, was associated with d-serine-mediated cytotoxicity; these reactive oxygen species could be alleviated not only after NMDAR inhibition but also by NADPH oxidase (NOX) inhibition. Activation of protein kinase C (PKC)-δ and PKC-ζ is a downstream signal for NMDAR-mediated NOX activation because PKC inhibition diminishes the NOX activity that is induced by d-serine. Renal injury was further confirmed in male Wistar rats that intraperitoneally received d-serine but not l-serine. Peak changes in glucosuria, proteinuria, and urinary excretion of lactate dehydrogenase and malondialdehyde were found after 24 h of treatment. Persistent tubular damage was observed after 7 days of treatment. Cotreatment with the NMDAR blocker MK-801 for 24 h abolished d-serine-induced functional insufficiency and tubular damage. MK-801 attenuated renal superoxide formation by lowering NOX activity and protein upregulation of NOX4 but not NOX2. These results reveal that NMDAR hyperfunction underlies d-serine-induced renal injury via the effects of NOX4 on triggering oxidative stress.NEW & NOTEWORTHY Ionotropic N-methyl-d-aspartate receptors (NMDARs) are not only present in the nervous system but also expressed in the kidney. Overstimulation of renal NMDARs leads to oxidative stress via the signal pathway of calcium/protein kinase C/NADPH oxidase in d-serine-mediated tubular cell damage. Intervention of NMDAR blockade may prevent acute renal injury caused by d-serine.

Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys.

Short bowel (SB) increases the risk of kidney stones. However, the underlying mechanism is unclear. Here, we examined how SB affected renal oxalate and citrate handlings for in vivo hyperoxaluric rats and in vitro tubular cells. SB was induced by small intestine resection in male Wistar rats. Sham-operated controls had no resection. After 7 days of recovery, the rats were divided into control, SB (both fed with distilled water), ethylene glycol (EG), and SB+EG (both fed with 0.75% EG for hyperoxaluric induction) groups for 28 days. We collected the plasma, 24 h of urine, kidney, and intestine tissues for analysis. Hypocitraturia was found and persisted up to 28 days for the SB group. Hypocalcemia and high plasma parathyroid hormone (PTH) levels were found in the 28-day SB rats. SB aggravated EG-mediated oxalate nephropathy by fostering hyperoxaluria and hypocitraturia, and increasing the degree of supersaturation and calcium oxalate (CaOx) crystal deposition. These effects were associated with renal up-regulations of the oxalate transporter solute carrier family 26 (Slc26)a6 and citrate transporter sodium-dependent dicarboxylate cotransporter-1 (NaDC-1) but not Slc26a2. The effects of PTH on the SB kidneys were then examined in NRK-52E tubular cells. Recombinant PTH attenuated oxalate-mediated cell injury and up-regulated NaDC-1 via protein kinase A (PKA) activation. PTH, however, showed no additive effects on oxalate-induced Slc26a6 and NaDC-1 up-regulation. Together, these results demonstrated that renal NaDC-1 upregulation-induced hypocitraturia weakened the defense against Slc26a6-mediated hyperoxaluria in SB kidneys for excess CaOx crystal formation. Increased tubular NaDC-1 expression caused by SB relied on PTH.

Renal urothelial carcinoma with extended venous thrombus.

Vascular invasion is not uncommon histologically in patients with urothelial carcinoma (UC) arising from the renal pelvis or ureter, while tumor thrombus affecting the main renal vein or the inferior vena cava (IVC) is rare. Herein, we report a unique case of renal pelvic UC with extended IVC thrombus manifested as progressive swelling in the lower limbs.