Shedding and repair of renal cell membranes following drug-induced nephrotoxicity in humans

Abstract

Nephrotoxic drugs may account for approximately at least 20% of clinically observed cases of acute renal failure in whom tubular lethal or sublethal damage is a predominant finding. Acute toxic tubular cell injury is characterized by loss of cellular polarization, intrinsic energy deficiency, calcium overload, release of toxic proteases and free oxygen radicals, derangement of the cytoskeleton, and vacuolar transformation of brush border microvilli. These events may finally lead to irreversible cell death. Shedding of membrane enzymes and cytoskeletal components in urine (kidney tissue proteinuria) may serve as a noninvasive early marker for assessing tubular cell injury. Successful recovery of renal function depends on early repair of lethally or sublethally damaged nephrons, in which intrinsic nephrogenic adaptive and proliferative responses cooperate in concert with auto/para/-juxtacrine growth promoting factors and cytokines. Exogenously administered growth factors may enhance renal cell recovery, as shown in animal models. Increased expression of immediate early genes in tubular cells after renal injury reflects the ongoing mitogenic activity necessary for reepithelialization and remodeling (new, polarized, differentiated cells). Further progress in understanding the molecular mechanisms of renal tubular injury will probably influence the diagnostic modalities and therapeutic approaches to acute drug induced renal failure.

Mode of cytotoxic action of nephrotoxic agents: oxidative stress and glutathione‐dependent enzyme

“…To examine the cytotoxic effects of various nephrotoxic agents, LLC‐PK 1 cells were cultured with HgCl 2 (30 µ m ), glycerol (2.5%), cisplatin (100 µ m ), gentamicin (5 mg/mL), and cyclosporin A (3 µ m ) for 72 h, and the cell number/viability determined. The concentrations used here were previously reported to have adverse effects on renal cells [1,2] and have also been confirmed to be effective in our pilot study. As a result, all five agents were capable of inducing a significant reduction in viability ( P < 0.01) compared with untreated control cells.…”

“…Acute renal cell injury or failure at the cellular level has been shown to be multifocal, resulting from loss of cellular polarization, intrinsic energy deficiency, calcium overload, release of toxic proteases and oxygen free radicals, derangement of the cell cytoskeleton, and vacuolar transformation of brush‐border microvilli [1]. These events could seemingly lead to irreversible cellular injury, although the exact mechanism is not fully elucidated.…”

Dose-Dependent Chemopreventive Effect of Methanol Extract of Carica papaya Seed on Potassium Bromate- Induced Nephrotoxicity in Rats

“…(1) There could be direct loss of BBM or enzyme molecules into the lumen of the tubule following the toxic attacks by KBrO 3 , as it was reported for some nephrotoxicants by other researchers [28,29] and (2) There could be enzymes inactivation due to conformational changes in the molecular structure of the BBM enzymes. Earlier researchers have reported oxidative modification of amino acid side chains of enzyme protein by reactive oxygen species that was generated by KBrO 3 toxicity and consequent inactivation of the BBM enzymes [30,31,32] BBM forms the major lining of the epithelial cells of the proximal tubule of the kidney and it was reported to be the first barrier for various solutes during absorption in the kidney.…”

Detection of renal brush border membrane enzymes for evaluation of renal injury in neonatal scleredema

“… 19 Shedding of RBBME reflects the acute tubular injury that can be detected before any other symptoms has been developed. 20 Assay of RBBME has been used in evaluation of drug-induced nephrotoxicity, 21 post transplantation kidney function surveillance, 22 etc.…”