Dear Editor; Recently, we conducted a preclinical investigation to find the ameliorative properties of metformin on renal biochemical and histologic alterations of gentamicin-induced kidney damage in male Wistar rats (1). In this investigation, attenuation of gentamicin-induced acute kidney injury was found. Likewise, Taheri et al. conducted a study on the effects of metformin on renal TUBULAR CELLS after unilateral ischemia reperfusion in rats’ kidney. They observed that metformin provided kidney protection against ischemia and reperfusion-induced injury (2). They concluded that metformin has tissue-protective effect through activation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (2). More recently we conducted a study on 70 male Wistar rats to test the efficacy of coadministrating garlic extract and metformin in prevention of gentamicin-induced renal TUBULAR damage in Wistar rats (3). The result of this study showed that metformin, garlic juice, or their combination had both curative and protective effects on gentamicin-induced kidney injury. In addition, Kim et al...

Objective: Proximal TUBULAR epithelial CELLS (PTCs) perform a large variety of transport, metabolic and endocrinolgic functions in the kidney. Due to their role in drug transport and metabolism, this cell type is the major target for drug-induced toxic effects. Hence, PTCs are applied inin vitro nephrotoxicology and are also employed in bioartificial kidneys. Primary human CELLS are most interesting for both of these applications. However, the cell source is limited and interdonor variability is a point of concern. Human stem cell-derived PTC-like CELLS would be an attractive alternative, but protocols for the generation of stem cell-derived PTC-like CELLS have not been established. We have developed a protocol for the generation of PTC-like CELLS, and performed a thorough characterization of the CELLS.Materials and Methods: In order to obtain PTC-like CELLS, human embryonic stem CELLS (hESCs) were cultivated for 20 days on Matrigel in renal epithelial growth medium with various supplements and growth factors. Subsequently, CELLS were characterized byin vitro and in vivoassays and in ex vivo organ culture.Results: hESC-derived PTC-like CELLS formed epithelia in vitroand integrated into renal TUBULAR epithelia in ex vivoorgan cultures. The CELLS displayed the characteristic morphology and formed TUBULAR structuresin vitro andin vivo. Furthermore, PTC-like CELLS expressed various markers specific for PTCs and their precursors, and their gene expression patterns were remarkably similar to those of primary human PTCs. Markers specific for other types of renal CELLS were not expressed. PTC-like CELLS showed functional characteristics of PTCs, and they were functional in bioreactors mimicking the conditions in bioartificial kidneys.Conclusion: PTC-like CELLS were successfully generated from hESCs. The usefulness of these stem cell-derived CELLS for applications in kidney tissue engineering andin vitrotoxicology will be addressed.

Objective(s): Cisplatin is an effective antineoplastic agent; its clinical utility, however, is limited by a few salient toxic side effects like nephrotoxicity. This study aimed to determine the potential protective effects of tangeretin, a citrus-derived flavonoid, against renal TUBULAR cell injury in cisplatin-induced renal toxicity of rats. Materials and Methods: Tangeretin was injected intraperitoneally at 2. 5 and 5 mg/kg doses for 10 days, and a single dose of cisplatin (8 mg/kg) was injected on the 7th day. Tests of kidney function and TUBULAR injury in renal tissues and urine together with oxidative stress and inflammation markers were examined. Results: Tangeretin ameliorated cisplatin-induced elevations in serum creatinine, BUN, and histopathologic changes. It also attenuated kidney oxidative stress elicited by cisplatin as demonstrated by reduced MDA and increased GSH, CAT, and SOD activities, elevated Nrf2 expression and protein levels of its downstream effectors, HO-1 and NQO-1. Tangeretin further alleviated inflammation evoked by cisplatin as indicated by reduced NF-κ B p65 subunit phosphorylation with a simultaneous decrement in its downstream effectors IL-1β and TNF-α expression and protein levels. Moreover, it declined caspase-3 protein levels and TUNEL positive CELLS in the kidneys, the markers of apoptosis and DNA fragmentation, thus improving renal endurance. Additionally, tangeretin mitigated renal levels of KIM-1 and NGAL, as well as urinary cystatin C and β 2-microglobulin concentrations, the markers of renal TUBULAR injury. Conclusion: Collectively, these data signify the binary profit of tangeretin: enhancement of renal protective mechanisms against cisplatin and attenuation of renal TUBULAR cell injuries induced by the agent.

Introduction. Atorvastatin has antioxidant activity and has been reported to increase blood antioxidant capacity. This study aimed to evaluate the effect of different doses of atorvastatin on gentamicininduced kidney injury. Materials and Methods. In this experimental study, 30 male Wistar rats were designated into 6 equal groups for a 7-day period of intraperitoneal injections of gentamicin and atorvastatin. Group 1 received gentamicin, 80 mg/kg. Group 2 received phosphate buffer as the vehicle of atorvastatin. All rats in groups 3, 4, and 5 received gentamicin, 80 mg/kg/d, and then, after a 1-hour interval, atorvastatin was injected for 7 days as follow: group 3, 10 mg/kg/d; group 4, 50 mg/kg/d; and group 5, 150 mg/kg/d. Rats in group 6 received only 150 mg of atorvastatin. On the 8th day, blood samples were collected for evaluation of creatinine and blood urea nitrogen levels, and the animals’ kidneys were dissected out for histopathological examinations. Results. Morphological damages to the TUBULAR CELLS in groups 3 and 4 were less than the those in groups 1 and 5. Injuries to the renal TUBULAR CELLS in the rats of group 5 (gentamicin and atorvastatin, 150 mg/kg/d) and in group 6 (atorvastatin 150 mg/kg/d alone) were more extensive than those in group 1. Conclusions. The none– dose-dependent effect of atorvastatin in inducing renal TUBULAR cell protection and renal TUBULAR toxicity of atorvastatin in higher dose suggest administration of low-dose atorvastatin in critical conditions associated with renal TUBULAR cell protection.

Introduction. Calcineurin-binding protein 1 (Cabin1) interacts with calcineurin and p53, but its function in renal TUBULAR epithelial cell (RTEC) is unclear. We established 5/6 nephrectomized rats and angiotensin II-induced injury to the RTECs in vitro, to observe the expression of Cabin1 during RTEC injury. Materials and Methods. Sprague-Dawley rats were sacrificed at 4 and 8 weeks after 5/6 nephrectomy. Renal pathology and mitochondrial damage were detected by light and electrical microscope. The distribution of E-cadherin and α-smad were detected by indirect immunofluorescence staining. Cabin1 protein expression was detected by Western blot. Results. Obvious tubulointerstitial fibrosis was found in the nephrectomized rats at 8 weeks after 5/6 nephrectomy, accompanied by the increasing levels of creatinine, as well as the disruption of E-cadherin and overexpression of α-smad in RTECs. Moreover, the mitochondria became swollen and mitochondrial cristae were disrupted and poorly defined in the RTECs. Compared to the sham-operated rats, Cabin1 protein expression was significantly increased at 8 weeks after 5/6 nephrectomy, while angiotensin II-induced Cabin1 protein expression significantly increased 48 hours after stimulation in normal rat kidney epithelial CELLS. Conclusions. Injury to the RTEC and Cabin1 protein overexpression occurred in a time-dependent manner both in vitro and in vivo. Cabin1 may become a potential molecular target in RTEC injury.

Acute renal damage mainly develops following toxic or ischemic insults and is defined as acute. These damages have largely been attributed to oxidative stress. Recently much attention has been directed toward decreased renal TUBULAR cell regeneration during TUBULAR cell injury. Antioxidants have recently been the focus of researchers and scientists for prevention and treatment of various oxidative stress-related conditions, including renal toxicities. Although free radicals are known to contribute in kidney injury and abundant researches, particularly laboratory trials, have shown the beneficial effects of antioxidants against these complications, long term clinical trials do not uniformly confirm this matter, especially for single antioxidant consumption such as vitamin C. The aim of this paper is to discuss the possible explanation of this matter.

Objective: One of the severe complications and well-known sources of end stage renal disease (ESRD) from diabetes mellitus is diabetic nephropathy (DN). Exosomes secreted from diverse CELLS are one of the novel encouraging therapies for chronic renal injuries. In this study, we assess whether extracted exosomes from kidney TUBULAR CELLS (KTCs) could prevent early stage DN in vivo. Materials and Methods: In this experimental, exosomes from conditioned medium of rabbit KTCs (RK13) were purified by ultracentrifuge procedures. The exosomes were assessed in terms of morphology and size, and particular biomarkers were evaluated by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Western blot, atomic force microscopy (AFM) and Zetasizer Nano analysis. The rats were divided into four groups: DN, control, DN treated with exosomes and sham. First, diabetes was induced in the rats by intraperitoneial (i. p. ) administration of streptozotocin (STZ, 50 mg/kg body weight). Then, the exosomes were injected each week into their tail vein for six weeks. We measured 24-hour urine protein, blood urea nitrogen (BUN), and serum creatinine (Scr) levels with detection kits. The histopathological effects of the exosomes on kidneys were evaluated by periodic acid-Schiff (PAS) staining and expressions of miRNA-29a and miRNA-377 by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The KTC-Exos were approximately 50-150 nm and had a spherical morphology. They expressed the CD9 and CD63 specific markers. Intravenous injections of KTC-Exos potentially reduced urine volume (P<0. 0001), and 24-hour protein (P<0. 01), BUN (P<0. 001) and Scr (P<0. 0001) levels. There was a decrease in miRNA-377 (P<0. 01) and increase in miRNA-29a (P<0. 001) in the diabetic rats. KTC-Exos ameliorated the renal histopathology with regulatory changes in microRNAs (miRNA) expressions. Conclusion: KTC-Exos plays a role in attenuation of kidney injury from diabetes by regulating the miRNAs associated with DN.