Cisplatin-induced Nephropathy Research Articles

CHIP drives proteasomal degradation of NUR77 to alleviate oxidative stress and intrinsic apoptosis in cisplatin-induced nephropathy

Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrated that CHIP was abundantly expressed in the renal proximal tubular epithelia, and its expression was downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated NUR77 to promote its degradation, which consequently shielded BCL2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrated that CHIP interacted with NUR77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicated that CHIP ubiquitinated and degraded its substrate NUR77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI.

CBGA ameliorates inflammation and fibrosis in nephropathy

Cannabidiol (CBD) is thought to have multiple biological effects, including the ability to attenuate inflammatory processes. Cannabigerols (CBGA and its decarboxylated CBG molecule) have pharmacological profiles similar to CBD. The endocannabinoid system has recently emerged to contribute to kidney disease, however, the therapeutic properties of cannabinoids in kidney disease remain largely unknown. In this study, we determined whether CBD and CBGA can attenuate kidney damage in an acute kidney disease model induced by the chemotherapeutic cisplatin. In addition, we evaluated the anti-fibrosis effects of these cannabinoids in a chronic kidney disease model induced by unilateral ureteral obstruction (UUO). We find that CBGA, but not CBD, protects the kidney from cisplatin-induced nephrotoxicity. CBGA also strongly suppressed mRNA of inflammatory cytokines in cisplatin-induced nephropathy, whereas CBD treatment was only partially effective. Furthermore, both CBGA and CBD treatment significantly reduced apoptosis through inhibition of caspase-3 activity. In UUO kidneys, both CBGA and CBD strongly reduced renal fibrosis. Finally, we find that CBGA, but not CBD, has a potent inhibitory effect on the channel-kinase TRPM7. We conclude that CBGA and CBD possess reno-protective properties, with CBGA having a higher efficacy, likely due to its dual anti-inflammatory and anti-fibrotic effects paired with TRPM7 inhibition.

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Cisplatin is a potent first-line therapy for many solid malignancies, such as breast, ovarian, lung, testicular, and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects; however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatin-induced AKI. Male wild-type C57BL6 (WT) and Faah-/- mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later. Faah-/- mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers, and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (palmitoylethanolamide and oleoylethanolamide), attenuated nuclear factor-κB/p65 activity, DNA damage markers p53 and p21, and decreased expression of the inflammatory cytokine interleukin-1β, as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity. SIGNIFICANCE STATEMENT: Mice lacking the Faah gene are protected from cisplatin-induced inflammation, DNA damage response, tubular damage, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity.

Effect of Cisplatin on Renal Iron Homeostasis Components: Implication in Nephropathy.

Cisplatin is an important chemotherapeutic drug for the treatment of solid tumors but often causes nephropathy as part of the off-target toxicity. Iron accumulation and related damage were implicated in cisplatin-induced kidney injury. However, the role of cisplatin in the renal iron sensing mechanism and its target genes responsible for iron uptake, storage, and release have not been investigated. Cellular iron homeostasis is controlled by the interaction of iron regulatory proteins (IRP1 and IRP2) and iron-responsive elements (IREs) present in the untranslated regions of iron transport and storage components. Here, we report that cisplatin does not influence the expressions of IRP targets such as transferrin receptor-1 (TfR1), divalent metal transporter-1 (DMT1), and ferroportin in renal cells despite the increased heme oxygenase-1 (HO-1) level. Ferritin subunits (Ft-H and Ft-L) are elevated in different magnitudes due to the increased mRNA expression. Intriguingly, a higher expression of Ft-L mRNA is detected than that of Ft-H mRNA. The inability of cisplatin in altering the IRE–IRP interaction is confirmed by examining IRE-containing luciferase activity, RNA electrophoretic mobility shift assay, and activation of IRPs. The labile iron pool is depleted but reversed by silencing of either Ft-H or Ft-L, suggesting increased iron storage by ferritin. Silencing of Ft-H or Ft-L promotes cell death, suggesting that ferritin acts to protect the renal cells from cisplatin-mediated toxicity. A differential increase of transcripts and equivalent increase of proteins of Ft-H and Ft-L and unaltered TfR1 and DMT1 transcripts are found in the kidneys of cisplatin-treated rats along with iron accumulation. Our results reveal that cisplatin does not influence the IRE–IRP interaction despite alteration of the cellular iron pool in renal cells. This insensitivity of the IRE–IRP system may be implicated in the accumulation of iron to contribute to cisplatin-induced nephropathy.

Receptor of Advanced Glycation End Products Deficiency Attenuates Cisplatin-Induced Acute Nephrotoxicity by Inhibiting Apoptosis, Inflammation and Restoring Fatty Acid Oxidation.

Cisplatin is a widely used and potent anti-neoplastic agent, but severe and inescapable side effects in multiple normal tissues and organs limit its application, especially nephrotoxicity. Molecular mechanisms of cisplatin nephrotoxicity involve mitochondrial damage, oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, necroptosis, etc. Receptor of advanced glycation end products (RAGE) is a multiligand pattern recognition receptor, engaged in inflammatory signaling and mitochondrial homeostasis. Whether inhibition of RAGE alleviates cisplatin-induced nephropathy has not been investigated. Here, we revealed that RAGE deficiency attenuates cisplatin-induced acute nephrotoxicity, as evidenced by reduced apoptosis, inflammation, lipid accumulation, restored mitochondrial homeostasis and fatty acid oxidation in renal tubular epithelial cells (TECs). In vitro studies showed that, the RAGE-specific inhibitor FPS-ZM1 attenuated the cisplatin-induced decrease of cell viability and fatty acid oxidation in the normal rat renal TEC line NRK-52E cells. Taken together, RAGE knockout mitigated cisplatin-induced acute nephrotoxicity by inhibiting apoptosis, inflammation, and restoring fatty acid oxidation in TECs, suggesting that RAGE inhibition could be a therapeutic option for cisplatin-induced acute nephrotoxicity.

Protective role of zinc oxide nanoparticles in kidney injury induced by cisplatin in rats

Cisplatin used as chemotherapy for various cancers may leads to accumulation of platinum within the kidney and disturb its function. Zinc oxide nanoparticles (ZnO-NPs) are of low toxicity nanomaterials and have many medical fields so this study aims to indicate ZnO-NPs effect in kidney injury induced by cisplatin. Adult male rats were pre-injected with one dose of ZnO-NPs (5 mg/kg IP) and after 2 h from injection, the rats were injected with also only one dose of cisplatin (6 mg/kg IP) and two additional groups were served as controls treated with either ZnO-NPs or cisplatin only, respectively, and normal control was involved and euthanization occurred after 7 and 12 days. Cisplatin-induced nephropathy increased kidney function parameters; serum creatinine, blood urea nitrogen and microalbuminuria. Conversely, these parameters were down regulated after ZnO-NPs treatment. ZnO-NPs reversed the decrease of renal superoxide dismutase, catalase and glutathione reductase and the increase of renal malondialdehyde induced by cisplatin. In addition, the annexin V demonstrated that the proportion of viable cells was significantly elevated and the proportion of apoptotic and necrotic cells significantly reduced. Also, the level of renal transforming growth factor beta 1 decreased in group pre-treated with ZnO-NPs. The Nuclear factor-E2-related factor, heme oxygenase-1 and endothelial nitric oxide synthase expression genes were up regulated while Bcl-2-associated X protein expression was down regulated in kidney tissue via ZnO-NPs. Histopathological and immunohistochemical observations were context with these findings. In conclusion, ZnO-NPs treatment revealed renoprotective effect against cisplatin drug, probably via its antioxidant, anti-inflammatory and antiapoptotic properties.

Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration

The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the CAP protected the kidney even after injury in a cisplatin-induced nephropathy model. Considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury.

Canagliflozin reduces cisplatin uptake and activates Akt to protect against cisplatin-induced nephrotoxicity.

Cisplatin is a widely used chemotherapy drug with notorious nephrotoxicity. Na+-glucose cotransporter 2 inhibitors are a class of novel antidiabetic agents that may have other effects in the kidneys besides blood glucose control. In the present study, we demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy in C57BL/6 mice and suppresses cisplatin induced renal proximal tubular cell apoptosis in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38 and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by kidney tissues in mice and renal tubular cells in culture. In addition, canagliflozin enhanced the activation of Akt and inhibited the mitochondrial pathway of apoptosis during cisplatin treatment. The protective effect of canagliflozin was diminished by the phosphatidylinositol 3-kinase/Akt inhibitor LY294002. Notably, canagliflozin did not affect the chemotherapeutic efficacy of cisplatin in A549 and HCT116 cancer cell lines. These results suggest a new application of canagliflozin for renoprotection in cisplatin chemotherapy. Canagliflozin may protect kidneys by reducing cisplatin uptake and activating cell survival pathways.

7-Hydroxycoumarin protects against cisplatin-induced acute kidney injury by inhibiting necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation

Background7-Hydroxycoumarin (7-HC), also known as umbelliferon, is commonly found in Chinese herbs (e.g. Eucommiae Cortex, Prunellae Spica, Radix Angelicae Biseratae). Previous laboratory studies have indicated that 7-HC has anti-inflammatory, anti-oxidative, and anti-tumor effects. Cisplatin is a widely used chemotherapeutic agent for cancer. Nephrotoxicity is one of the limiting side effects of cisplatin use. PurposeThis study aimed to evaluate the renoprotective effect of 7-HC in a cisplatin-induced acute kidney injury (AKI) mouse model. MethodsAKI was induced in male C57BL/6 mice (aged 6–8 weeks) by a single intraperitoneal injection of cisplatin at 20 mg/kg. The mice received 7-HC at 30, 60, and 90 mg/kg intraperitoneally before or after cisplatin administration. Renal function, necroptosis, and cell proliferation were measured. Mechanisms underlying the reno-protective effect of 7-HC were explored in renal tubular epithelial cells treated with or without cisplatin. ResultsIn-vivo experiments showed that 7-HC significantly improved the loss in kidney function induced by cisplatin, as indicated by lower levels of serum creatinine and blood urea nitrogen, in AKI mice. Consistent herewith, cisplatin-induced tubular damage was alleviated by 7-HC as shown by morphological (periodic acid–Schiff staining) and kidney injury marker (KIM-1) analyses. We found that 7-HC suppressed renal necroptosis via the RIPK1/RIPK3/MLKL pathway and accelerated renal repair as evidenced by the upregulation of cyclin D1 in cisplatin-induced nephropathy. In-vitro experiments showed that knockdown of Sox9 attenuated the suppressive effect of 7-HC on KIM-1 and reversed the stimulatory effect of 7-HC on cyclin D1 expression in cisplatin-treated HK-2 cells, indicating that 7-HC may protect against AKI via a Sox9-dependent mechanism. Conclusion7-HC inhibits cisplatin-induced AKI by suppressing RIPK1/RIPK3/MLKL-mediated necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation. 7-HC may serve as a preventive and therapeutic agent for AKI.

Kidney therapeutic potential of peptides derived from the bromelain hydrolysis of green peas protein.

Kidney disease is a global health problem that needs a solution to its therapy. In the previous study, we found that protein hydrolysate of green peas origin of Indonesia hydrolysed by bromelain (PHGPB) showed improve kidney function in cisplatin-induced nephropathy rats. In this study, we investigated the effect of PHGPB to obtain effective dose that exerts a therapeutic effect on chronic kidney disease (CKD) based on reducing urea and creatinine levels and to elucidate its mechanism of action. Two sets of experiments were conducted: (1) characteristics and proteomic profile of PHGPB, (2) in vivo test of PHGPB in gentamycin-induced Wistar rats, including urea and creatinine measurements, activities of antioxidant and kidney-related peptides (ANP, COX-1, and renin). PHGPB showed three bands under 10 kDa using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and contained 10 identified proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in urea and creatinine levels were found between all PHGPB treatments and positive controls (P<0.01). The lowest levels of urea and creatinine that were validated by high super oxide dismutase (SOD) activity and atrial natriuretic peptide (ANP) level were obtained in the 200 mg/day PHGPB treatment. However, the mean renin level was high and cyclooxygenase-1 (COX-1) level did not exceed positive and negative control levels. PHGPB at dose 200 mg/kgBW shows a potential CKD therapeutic effect that is dose-dependent. Higher PHGPB dose corresponds to better effect on kidney function by increasing antioxidant activity and ANP levels in gentamycin-induced Wistar rats.

Coleus amboinicus extract increases transforming growth factor-1β expression in Wistar rats with cisplatin-induced nephropathy.

Background and Aim:Coleus amboinicus (CA) plants are known to exert antibacterial and anti-inflammatory effects and demonstrate antiproliferative effects against cancer cells. This study aimed to investigate the activity of CA extract on the expression of transforming growth factor-1β (TGF-1β) in cisplatin-induced nephropathy in Wistar rats (Rattus norvegicus).Materials and Methods:CA was obtained from fresh leaves of CA and was extracted using 96% ethanol maceration. This blinded, controlled, randomized post-test study assigned 24 Wistar rats to three groups (n=8). Negative controls received normal saline (P0), nephropathy was induced in rats by cisplatin (5 mg/kg, IP) (P1), and treated with ethanolic coleus extract (500 mg/kg, PO) (P2), respectively, for 7 days. Nephropathy was induced on the 4th day. All rats were sacrificed on the 8th day for blood and kidney sample collection. Concentrations of blood urea nitrogen (BUN), creatinine, and alkaline phosphatase were analyzed using colorimetric analysis. A semi-quantitative analysis was performed on sectioned kidneys to determine the numbers of positive cells for TGF-1β expression and to evaluate structural and functional alterations in the kidneys using histopathological and immunohistochemical staining.Results:The concentrations of BUN, creatinine, and alkaline phosphatase from blood samples in the treatment group were significantly lower than those of the control group (p<0.05). Morphological evaluation of the tubular interstitium and glomeruli revealed that necrotic, degenerating, and infiltration of cells significantly decreased in the treatment group compared to the control group (p<0.05). The mean immunostaining scores indicating the presence of TGF-1β were 7.8 in the ethanolic coleus extract group, 3 in the induction group, and 2.3 in the control group. The expression scores for TGF-β1 were significantly different between the ethanolic coleus extract treatment and control group (p<0.05).Conclusion:Our results suggest that in Wistar rats with cisplatin-induced nephropathy, CA extract inhibits pathological lesions by regulating the renal expression of TGF-1β in areas containing the renal tubules and glomeruli.

Hypolipidemic Effects of Pea Protein Hydrolysates on Lipid Profile and Uric Acid in Cisplatin-Induced Nephropathy Rats

The usage of Cisplatin (CP) can cause side effects such as toxicity and impaired kidneyfunction. Poor kidney function causes dyslipidemia and hyperuricemia. Researchers in Canadastate that pea protein hydrolysates can improve kidney function. The aim was to examine thehypolipidemic effect of 8 types of pea protein hydrolysate on lipid profiles and uric acid in CPinduced rats in purpose to find protein sources origin of Indonesia for kidney therapy. This is atrue experimental study using fifty female Wistar rats divided into 10 treatment groups.Weadministered 8 types of pea protein hydrolysate for 30 days. On day 7 all rats (except negativecontrol) were induced CP intraperitoneally. Study parameters was evaluated on days 12 and30. In general, all treatments showed good hypolipidemic effects, and differed significantly fromCP group (p &lt;0.01). The group that showed lowest total cholesterol, LDL and triglycerideresults is yellow pea protein hydrolysate Neutrase; HDL: green peas protein hydrolysatebromelain, uric acid: protein hydrolysate of pea protein isolate bromelain. As conclusion,protein hydrolysates of pea has good hypolipidemic effects on Lipid profile and Uric Acid inCP-induced nephropathy Rats.&#x0D; Keywords: protein hydrolysates, green peas, neutrase, bromelain, lipid profiles

MDM2 inhibitor ameliorates cisplatin-induced nephropathy via NFκΒ signal inhibition.

Cisplatin is a platinum‐containing chemotherapeutic drug, which is widely used and highly effective. While effective against tumors, its use is limited by severe side effects such as nephrotoxicity and bone marrow suppression. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and inhibition of MDM2 can suppress tumor cell growth. However, independent of p53, MDM2 acts as a co‐transcription factor for nuclear factor‐κB (NFκB), whose signaling can be involved in cisplatin‐induced tubular injury. We therefore examined the effects of MDM2 inhibitor on cisplatin cytotoxicity. In order to induce acute kidney injury and to investigate MDM2 inhibitory effects, we injected cisplatin into rats with or without the MDM2 inhibitor, DS‐5272, and analyzed kidney physiology/histology and NFκB signaling. Serum creatinine was significantly lower in the DS‐5272 group than in the vehicle group on day 3 (0.55 ± 0.069 vs 0.70 ± 0.072 mg/dL, P < 0.05). DS‐5272 also significantly decreased kidney injury molecule‐1 (KIM‐1) expression, improved tubular injury, and decreased apoptotic cells. Western blotting showed that cisplatin increased NFκB phosphorylation in kidneys, which was significantly suppressed by DS‐5272. In vitro, we treated HEK 293 cells with cisplatin, in the absence or presence of DS‐5272, and examined cytotoxicity and NFκB transcriptional activity. DS‐5272 co‐treatment reduced both cisplatin‐induced cell death and NFκB transcriptional activity. Collectively, these findings suggest that DS‐5272 can ameliorate cisplatin nephrotoxicity via NFκB signal inhibition.

Oral deferiprone administration ameliorates cisplatin-induced nephrotoxicity in rats.

Cisplatin is one of the widely used antitumour agents with major clinical side effect, nephrotoxicity. We showed the role of iron in cisplatin-induced nephrotoxicity that entrance to the cell via transferrin receptor (TfR) as a gatekeeper for iron uptake. We also examined the effect of iron chelator deferiprone against this toxicity. Thirty male Wistar rats were randomly divided into six groups. Group I (saline orally for 10days); group II (saline orally for 10days plus single injection of cisplatin 7mg/kg, intraperitoneally on 5th day); groups III, IV and V (deferiprone 50, 100 and 200mg/kg orally for 10days, respectively, plus cisplatin on 5th day). Group VI (deferiprone, orally). Deferiprone provided functional and significant histological-proven protection in group IV. Deferiprone attenuated the increased creatinine, BUN, malondialdehyde and iron concentrations in cisplatin-injected animals. The increased amounts of TfR and decreased levels of HIF-1α and related anti-apoptotic genes expression in cisplatin-treated animals were improved by deferiprone. The results supported a role for iron in cisplatin-induced nephrotoxicity and TfR may serve as an important source of iron. Based on these findings, deferiprone pretreatment may play a role in preventing cisplatin-induced nephropathy in cancer patient.

Ameliorating effect of Berberis lycium root bark extracts against cisplatin-induced nephropathy in rat

&lt;p&gt;The aim of this study was to investigate the sub-acute nephroprotective effect of &lt;em&gt;Berberis lycium&lt;/em&gt; root bark extracts against cisplatin-induced nephrotoxicity. Aqueous and methanol extracts (200 and 400 mg/kg) were co-administered with cisplatin (4 mg/kg) for 19 days. Results showed that cisplatin significantly (&lt;sup&gt;a&lt;/sup&gt;p&amp;lt;0.05) raised the serum creatinine, uric acid, urea level as well as tissue MDA level as compared to control group. It decreased GST activity, tGSH and catalase activity in rats. Both extracts significantly reduced the serum creatinine, urea and uric acid levels. Moreover, GST, CAT activity and tGSH content were significantly (p&amp;lt;0.05) increased and MDA level was decreased. Histopathological examination showed that both extracts efficiently reversed the morphological changes and damage induced by cisplatin. It is concluded that both extracts of &lt;em&gt;B. lycium&lt;/em&gt; root bark possess nephroprotective effect against cisplatin-induced nephrotoxicity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Video Clip of Methodology:&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;Histological study of rat kidney: 14 min 02 sec &lt;a href="https://www.youtube.com/v/QQGDo8e3HjQ"&gt;Full Screen&lt;/a&gt; &lt;a href="https://www.youtube.com/watch?v=QQGDo8e3HjQ"&gt;Alternate&lt;/a&gt;&lt;/p&gt;

Human Kidney-Derived Cells Ameliorate Acute Kidney Injury Without Engrafting into Renal Tissue.

Previous studies have suggested that CD133+ cells isolated from human kidney biopsies have the potential to ameliorate injury following intravenous (IV) administration in rodent models of kidney disease by integrating into damaged renal tissue and generating specialized renal cells. However, whether renal engraftment of CD133+ cells is a prerequisite for ameliorating injury has not yet been unequivocally resolved. Here, we have established a cisplatin‐induced nephropathy model in immunodeficient rats to assess the efficacy of CD133+ human kidney cells in restoring renal health, and to determine the fate of these cells after systemic administration. Specifically, following IV administration, we evaluated the impact of the CD133+ cells on renal function by undertaking longitudinal measurements of the glomerular filtration rate using a novel transcutaneous device. Using histological assays, we assessed whether the human kidney cells could promote renal regeneration, and if this was related to their ability to integrate into the damaged kidneys. Our results show that both CD133+ and CD133− cells improve renal function and promote renal regeneration to a similar degree. However, this was not associated with engraftment of the cells into the kidneys. Instead, after IV administration, both cell types were exclusively located in the lungs, and had disappeared by 24 hours. Our data therefore indicate that renal repair is not mediated by CD133+ cells homing to the kidneys and generating specialized renal cells. Instead, renal repair is likely to be mediated by paracrine or endocrine factors. Stem Cells Translational Medicine 2017;6:1373–1384

Mechanisms involved in the possible nephroprotective effect of rutin and low dose γ irradiation against cisplatin-induced nephropathy in rats

Cisplatin has demonstrated high antitumor efficacy. However, nephrotoxicity is a dose-limiting factor in its clinical use. The present study was designed to investigate the protective effect of rutin and low dose of irradiation (LDR) on cisplatin-induced nephrotoxicity in rats. Rats received rutin (200mg/kg/day, p.o) for 10 consecutive days and subjected to LDR (0.5Gy) 1day prior to cisplatin. Intraperitoneal administration of single dose of cisplatin (7.5mg/kg) was used to induce nephrotoxicity. Data showed that cisplatin caused elevation in serum creatinine and urea, disturbance in blood count, elevation in gene expression of tumor necrosis factor alpha, nuclear factor kappa B, interleukin-1β, caspase-3, mitochondrial cytochrome C and apoptosis-inducing factor in renal tissue. Moreover, it caused elevation in renal malondialdehyde accompanied by reduction in glutathione content. These effects were confirmed by histopathological examination. It was observed that LDR and rutin ameliorated the studied parameters. In conclusion, LDR could be considered as a novel approach for prophylaxis of cisplatin induced renal damage, also it augmented the nephroprotective effect of rutin via modulating the expression of inflammatory, oxidative stress and apoptotic mediators as well as histological changes in rats kidneys and hence might be valuable in improving the therapeutic index of cisplatin.

Ameliorative effect of lycopene effect on cisplatin-induced nephropathy in patient.

Background: Nephrotoxicity is one of the most important limitations of cisplatin-based chemotherapies which associated with many complications and high mortality rate. Objectives: To investigate the effect of lycopene on cisplatin-induced nephrotoxicity in patients with cancer. Patients and Methods: In this double-blind, randomized clinical trial, 120 patients were randomly assigned to two groups, case (treated with lycopene + standard regimen of kidney injury prevention) and control (treated with only the standard regimen of kidney injury prevention). Lycopene was orally taken from 24 hours before to 72 hours after cisplatin administration. Blood urea nitrogen (BUN), serum creatinine (Cr), and glomerular filtration rate (GFR) were measured and recorded. The data were analyzed using SPSS. Results: Changes in Cr were not significantly different between the two groups (P = 0.131). However, a significant decreasing trend was seen in GFR during the study, which was more marked in the control group (P = 0.004). BUN significantly decreased during the study (P = 0.002), and a significant decrease of BUN on the day three in both groups was seen (P = 0.001). However, BUN increased in the case group on the day 21 of treatment. The corresponding increase was less marked in the control group. Conclusions: Lycopene can be considered a useful adjuvant therapy to decrease the complications due to cisplatin-induced nephrotoxicity in patients with cancer.

Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage.

Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.

Vanadium(III)-L-cysteine protects cisplatin-induced nephropathy through activation of Nrf2/HO-1 pathway

Cisplatin (CDDP) is one of the first-line anticancer drugs; however, the major limitation of CDDP therapy is development of nephrotoxicity (25–35% cases), whose precise mechanism mainly involves oxidative stress, inflammation and cell death. Therefore, in search of a potential chemoprotectant, an organovanadium complex, viz., vanadium(III)-L-cysteine (VC-III) was evaluated against CDDP-induced nephropathy in mice. CDDP was administered intraperitoneally (5 mg/kg b.w.) and VC-III was given by oral gavage (1 mg/kg b.w.) in concomitant and pre-treatment schedule. The results showed that VC-III administration reduced (p < 0.001) serum creatinine and blood urea nitrogen levels, suggesting amelioration of renal dysfunction. VC-III treatment also significantly (p < 0.001) prevented CDDP-induced generation of reactive oxygen species, reactive nitrogen species, and onset of lipid peroxidation in kidney tissues of the experimental mice. In addition, VC-III also substantially (p < 0.001) restored CDDP-induced depleted activities of the renal antioxidant enzymes such as, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione (reduced) level. Furthermore, histopathological study also confirmed the renoprotective efficacy of VC-III. Western blotting analysis appended by immunohistochemical data showed that VC-III treatment quite effectively reduced the expression of proinflammatory mediators such as, NFκβ, COX-2 and IL-6. VC-III administration also stimulated Nrf2-mediated antioxidant defense system by promotion of downstream antioxidant enzymes, such as HO-1. Moreover, treatment with VC-III significantly (p < 0.001) enhanced CDDP-mediated cytotoxicity in MCF-7 and NCI-H520 human cancer cell lines. Thus, VC-III can serve as a suitable chemoprotectant and increase the therapeutic window of CDDP in cancer patients.