Rosiglitazone reverses tenofovir-induced nephrotoxicity

Tenofovir disoproxil fumarate (TDF) is a first-line drug used in patients with highly active retroviral disease; however, it can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Because rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist induces the expression of many of these same transporters, we tested if the nephrotoxicity can be ameliorated by its use. High doses of TDF caused severe renal failure in rats accompanied by a reduction in endothelial nitric-oxide synthase and intense renal vasoconstriction; all of which were significantly improved by rosiglitazone treatment. Low-dose TDF did not alter glomerular filtration rate but produced significant phosphaturia, proximal tubular acidosis, polyuria and a reduced urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. A Fanconi`s-like syndrome was ruled out as there was no proteinuria or glycosuria. Rosiglitazone reversed TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. These studies suggest that rosiglitazone treatment might be useful in patients presenting with TFV-induced nephrotoxicity especially in those with hypophosphatemia or reduced glomerular filtration rate.

N-acetylcysteine protects against renal injury following bilateral ureteral obstruction

Background. Obstructive nephropathy decreases renal blood flow (RBF) and glomerular filtration rate (GFR), causing tubular abnormalities, such as urinary concentrating defect, as well as increasing oxidative stress. This study aimed to evaluate the effects of N-acetylcysteine (NAC) on renal function, as well as on the protein expression of aquaporin 2 (AQP2) and endothelial nitric oxide synthase (eNOS), after the relief of bilateral ureteral obstruction (BUO). Methods. Adult male Wistar rats were divided into four groups: sham (sham operated); sham operated + 440 mg/kg body weight (BW) of NAC daily in drinking water, started 2 days before and maintained until 48 h after the surgery; BUO (24-h BUO only); BUO + NAC-pre (24-h BUO plus 440 mg/kg BW of NAC daily in drinking water started 2 days before BUO); and BUO + NAC-post (24-h BUO plus 440 mg/kg BW of NAC daily in drinking water started on the day of BUO relief). Experiments were conducted 48 h after BUO relief. Results. Serum levels of thiobarbituric reactive substances, which are markers of lipid peroxidation, were significantly lower in NAC-treated rats than in the BUO group rats. The administration of NAC provided significant protection against post-BUO GFR drops and reductions in RBF. Renal cortices and BUO rats presented decreased eNOS protein expression of eNOS in the renal cortex of BUO group rats, whereas it was partially recovered in BUO + NAC-pre group rats. Urine osmolality was significantly lower in BUO rats than in sham group rats or NAC-treated rats, the last also presenting less interstitial fibrosis. Post-BUO downregulation of AQP2 protein expression was averted in the BUO + NAC-pre group rats. Conclusions. This study demonstrates that NAC administration ameliorates the renal function impairment observed 48 h after the relief of 24-h BUO. Oxidative stress is important for the suppression of GFR, RBF, tissue AQP2 and eNOS in the polyuric phase after the release of BUO.

Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression

Alexandre CS, Braganca AC, Shimizu MH, Sanches TR, Fortes MA, Giorgi RR, Andrade L, Seguro AC. Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression. Am J Physiol Renal Physiol 297: F916-F922, 2009. First published August 5, 2009; doi:10.1152/ajprenal.90256.2008.-Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodiumand water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg(2+) channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.

Histological and functional renal alterations caused by Bothrops alternatus snake venom: Expression and activity of Na(+)/K(+)-ATPase

Background: Acute renal failure is a serious complication of human envenoming by Bothrops snakes. The ion pump Na(+)/K(+)-ATPase has an important role in renal tubule function, where it modulates sodium reabsorption and homeostasis of the extracellular compartment. Here, we investigated the morphological and functional renal alterations and changes in Na(+)/K(+)-ATPase expression and activity in rats injected with Bothrops alternatus snake venom. Methods: Male Wistar rats were injected with venom (0.8 mg/kg, iv.) and renal function was assessed 6.24, 48 and 72 h and 7 days post-venom. The rats were then killed and renal Na(+)/K(+)-ATPase activity was assayed based on phosphate release from ATP; gene and protein expressions were assessed by real time PCR and immunofluorescence microscopy, respectively. Results: Venom caused lobulation of the capillary tufts, dilation of Bowman`s capsular space. F-actin disruption in Bowman`s capsule and renal tubule brush border, and deposition of collagen around glomeruli and proximal tubules that persisted seven days after envenoming. Enhanced sodium and potassium excretion, reduced proximal sodium reabsorption, and proteinuria were observed 6 h post-venom, followed by a transient decrease in the glomerular filtration rate. Gene and protein expressions of the Na(+)/K(+)-ATPase alpha(1) subunit were increased 6 h post-venom, whereas Na(+)/K(+)-ATPase activity increased 6 h and 24 h post-venom. Conclusions: Bothrops alternatus venom caused marked morphological and functional renal alterations with enhanced Na(+)/K(+)-ATPase expression and activity in the early phase of renal damage. General significance: Enhanced Na(+)/K(+)-ATPase activity in the early hours after envenoming may attenuate the renal dysfunction associated with venom-induced damage. (C) 2011 Elsevier B.V. All rights reserved.

Effect of Short-term High-Dose Creatine Supplementation on Measured GFR in a Young Man With a Single Kidney

It currently is unknown whether creatine supplementation is safe for people with or at risk of kidney disease. We report on the short-term effects of creatine supplementation on kidney function in a young man with a single kidney and mildly decreased glomerular filtration rate (GFR). A 20-year-old man who had undergone unilateral nephrectomy and presented with mildly decreased GFR without kidney damage underwent a trial with 35 days of creatine supplementation (20 g/d for 5 days followed by 5 g/d for the next 30 days) and had his kidney function monitored. After the intervention, (51)Cr-EDTA clearance (pre, 81.6 mL/min/1.73 m(2); post, 82.0 mL/min/1.73 m(2)), proteinuria (protein excretion: pre, 130 mg/d; post, 120 mg/d), and electrolyte levels were unchanged. Albuminuria, serum urea level, and estimated creatinine clearance were decreased (pre, 4.6 mg/d; post, 2.9 mg/d; pre, 37 mg/d; post, 28 mg/dL; and pre, 88 mL/min/1.73 m(2); post, 71 mL/min/1.73 m(2), respectively), whereas serum creatinine level was slightly increased (pre, 1.03 mg/dL; post, 1.27 mg/dL), falsely suggesting kidney function impairment. This prospective report suggests that short-term creatine supplementation may not affect kidney function in an individual with a single kidney, mild decreased GFR, and ingesting a high-protein diet (ie, 2.8 g/kg/d). This finding has great relevance considering that creatine-induced kidney disease has been a growing concern, even for healthy people. Am J Kidney Dis 55: e7-e9. (C) 2010 by the National Kidney Foundation, Inc.