Renoprotective Agent Research Articles

DIABETIC NEPHROPATHY AN OBVIOUS COMPLICATION IN LONG TERM TYPE 1 DIABETES MELLITUS: A CASE STUDY

Most overwhelming complications of Type 1 diabetes mellitus patients are responsible for complications related to the microvascular system most likely with kidney. In the kidney, hyperglycemia induced microangiopathy resulting not only thickening of the glomerular capillary basement membrane but also to the proliferation of the mesangial matrix and solidifying of the tubular basement membrane. Several biochemical and pathological, factors are concerned for the development of diabetic renal microangiopathy. These include the glomerular hyperperfusion and hyperfiltration, transformed morphology of podocytes accompanies these basement membrane modifications, Type IV collagen augmented synthesis following the hyperglycemia, and increased expression of tissue matrix metalloproteinase. The aim of this case review is to highlight the recent advances in understanding the pathogenesis, diagnosis, the overview and the potential renoprotective therapeutic agents that would prevent the development or the progression of diabetic nephropathy.

Penicilliumin B, a novel sesquiterpene methylcyclopentenedione from a deep sea-derived Penicillium strain with renoprotective activities

A novel sesquiterpene methylcyclopentenedione, penicilliumin B (1), was obtained from a deep sea-derived fungus Penicillium sp. F00120, together with three known sesquiterpene cyclohexenones (2–4). Penicilliumin B (1), presenting the first example with the sesquiterpene cyclopentenedione skeleton as natural products, was structurally determined by analysis of the NMR and MS spectroscopic data, while the absolute configurations were assigned by single-crystal X-ray experiments. The plausible biosynthetic pathway of the unusual cyclopentenone skeleton of 1 was proposed. Penicilliumin B (1), with low toxicity, was showed significant potential to inhibit the kidney fibrogenic action in vitro, by a mechanism dependent on disruption of oxidative stress, presenting a new type of promising renoprotective agent.

Inhibition of high glucose-induced inflammation and fibrosis by a novel curcumin derivative prevents renal and heart injury in diabetic mice

Hyperglycemia-induced inflammation and fibrosis have important roles in the pathogenesis of diabetic nephropathy and cardiomyopathy. With inflammatory cytokines and signaling pathways as important mediators, targeting inflammation may be an effective approach to new avenue for treating diabetic complications. J17, a molecule with structural similarities to curcumin, exhibited good anti-inflammatory activities by inhibiting LPS-induced inflammatory response in macrophages. However, its ability to alleviate hyperglycemia-induced injury via its anti-inflammatory actions remained unclear. Thus, we reported that J17 exerts significant inhibitory effects on hyperglycemia-induced inflammation and fibrosis in NRK-52E cells, H9C2 cells and a streptozotocin-induced diabetic mouse model. We also found that the anti-inflammatory and anti-fibrosis activities of J17 are associated with the inhibition of the P38 and AKT signal pathway, respectively. In vivo oral administration of J17 suppressed hyperglycemia-induced inflammation, hypertrophy and fibrosis, thereby reducing key markers for renal and cardiac dysfunction and improving in fibrosis and pathological changes in both renal and cardiac tissues of diabetic mice. The results of this study indicated that J17 can be potentially used as a cardio- and reno-protective agent and that targeting the P38 and AKT pathways may be an effective therapeutic strategy for diabetic complications.

Taurine decreased uric acid levels in hyperuricemic rats and alleviated kidney injury

Hyperuricemia can lead to direct kidney damage. Taurine participates in several renal physiological processes and has been shown as a renoprotective agent. It has been reported that taurine could reduce uric acid levels in diabetic rats, but to date there was no research on the effects of taurine on hyperuricemic rats with kidney injury. In present study, hyperuricemic rat models were induced by intragastric administration of adenine and ethambutol hydrochloride for 10 days, and taurine (1% or 2%) were added in the drinking water 7 days in advance for consecutively 17 days. The results showed that taurine alleviated renal morphological and pathological changes as well as kidney dysfunction in hyperuricemic rats. Taurine could efficiently decrease the elevated xanthine oxidase activities in hyperuricemic rats, indicating its effect on the regulation of uric acid formation. The reabsorption and secretion of uric acid are dependent on a number of urate transporters. Expressions of three urate transporters were significantly down-regulated in hyperuricemic rats, while taurine prevented the decrease of mRNA and protein expression levels of these urate transporters. The results indicate that taurine might play a role in the regulation of renal uric acid excretion. Therefore, taurine could be a promising agent for the treatment of hyperuricemia.

Effects of tanshinone IIA on the regulation of renal proximal tubular fibrosis.

The development of diabetes mellitus, along with its complications, is a chronic inflammatory response process. Chronic kidney diseases are characterized by renal fibrosis, and fibrosis is an important pathway for end‑stage renal failure. According to previous studies, high glucose (HG) has been demonstrated to be the most important fibrogenesis‑inducing agent. Tanshinone IIA is one of the main components isolated from Danshen (Salvia miltiorrhiza). Although tanshinoneIIA has been widely used for the treatment of cardiovascular diseases, the possible role of tanshinone IIA in fibrosis regulation remains to be elucidated and requires investigation. In the present study, renal proximal tubular epithelial cells (HK‑2) were treated with HG (30mM glucose) to determine whether tanshinone IIA (1, 10 and 50µM) had an effect on the regulation of renal cellular fibrosis. The results demonstrated that 50µM tanshinone IIA may exert optimal inhibitory effects on HG‑induced Snail, fibronectin, vimentin and α‑smooth muscle actin (α‑SMA) expression in HK‑2 cells after 48h. Tanshinone IIA also reversed HG‑induced morphological alterations in HK‑2 cells and inhibited an HG‑induced increase in fibronectin and α‑SMA mRNA and protein and an HG‑induced decrease in E‑cadherin. Furthermore, tanshinoneIIA suppressed an HG‑induced increase in Snail, which is a transcription factor that can suppress E‑cadherin expression. E‑cadherin is a major component of adherens junctions and a characteristic of epithelial integrity. Tanshinone IIA reversed HG‑induced increase in α‑SMA and decrease in E‑cadherin. These data suggest that tanshinone IIA has the potential to inhibit HG‑induced renal tubular epithelial cell fibrosis possibly through the epithelial‑myofibroblast transdifferentiation pathway. Therefore, tanshinone IIA may be considered a renoprotective agent for the treatment of renal fibrosis.

Protective Effect of Taurine on Mice with Doxorubicin-induced Acute Kidney Injury.

Nephrotic syndrome is still a therapeutic challenge because an effective treatment has not been developed. Evidence suggests that multidrug therapy is more effective than monotherapy in amelioration of renal injury. Therefore, we examined if taurine exerts a protective effect on doxorubicin-induced acute kidney injury in mice. Eight-week-old male Balb/c nude mice were used in this study. Taurine was orally administered at a dose of 50 mg/kg and 100 mg/kg body weight for 5 days. In the meantime, the mice were administered intraperitoneal injections of doxorubicin at 15 mg/kg body weight. At 24 h after the doxorubicin challenge, the response in the taurine-treated mice was compared with that in the vehicle-treated control mice. The doxorubicin-induced acute kidney injury model displayed a significant increase in the renal expression of apoptosis-related proteins (p53, phospho-p53, caspase 9, and caspase 3), whereas in the taurine-treated mice, the augmented expression of renal inflammation-related mRNAs such as NF-kB, COX-2, and iNOS was down-regulated. These results suggest that taurine acts as a renoprotective agent by inhibiting apoptosis and inflammation in the kidney of mice with doxorubicin-induced renal injury.

Attenuation of renal ischemic reperfusion injury by salvianolic acid B via suppressing oxidative stress and inflammation through PI3K/Akt signaling pathway.

Salvianolic acid B (SAB) is one the major phytocomponents of Radix Salvia miltiorrhiza and exhibit numerous health promoting properties. The objective of the current study was to examine whether SAB exerts a renoprotective effect by attenuating oxidative stress and inflammatory response through activating phosphatidylinositol 3-kinase/serine-threonine kinase B (PI3K/Akt) signaling pathway in a renal ischemic reperfusion rat model. Forty Sprague-Dawley male rats (250–300 g) were obtained and split into four groups with ten rats in each group. The right kidney of all rats was removed (nephrectomy). The rats of the Control group received only saline (occlusion) and served as a sham control group, whereas rats subjected to ischemic reperfusion (IR) insult by clamping the left renal artery served as a postitive control group. The other 2 groups of rats were pretreated with SAB (20 and 40 mg·kg-1·day-1) for 7 days prior IR induction and served as treatment groups (SAB 20+IR; SAB 40+IR). Renal markers creatinine (Cr) and blood urea nitrogen (BUN) were significantly lower in the groups that received SAB. Pretreatment with SAB appears to attenuate oxidative stress by suppressing the production of lipid peroxidation products like malondialdehyde as well as elevating antioxidant activity. The concentration of inflammatory markers and neutrophil infiltration (myeloperoxidase) were significantly decreased. Meanwhile, PI3K protein expression and pAkt/Akt ratio were significantly upregulated upon supplementation with SAB, indicating its renoprotective activity. Taken together, these results indicate that SAB can therapeutically alleviate oxidative stress and inflammatory process via modulating PI3K/Akt signaling pathway and probably ameliorate renal function and thus act as a renoprotective agent.

S-Nitrosoglutathione ameliorates acute renal dysfunction in a rat model of lipopolysaccharide-induced sepsis.

Sepsis induces an inflammatory response that results in acute renal failure (ARF). The current study is to evaluate the role of S-Nitrosoglutathione (GSNO) in renoprotection from lipopolysaccharide (LPS)-induced sepsis. Rats were divided to three groups. First group received LPS (5 mg/kg body weight), second group was treated with LPS + GSNO (50 μg/kg body weight), and third group was administered with vehicle (saline). They were sacrificed on day 1 and 3 post-LPS injection. Serum levels of nitric oxide (NO), creatinine and blood urea nitrogen (BUN) were analysed. Tissue morphology, T lymphocyte infiltrations, and the expression of inflammatory (TNF-α, iNOS) and anti-inflammatory (IL-10) mediators as well as glutathione (GSH) levels were determined. Lipopolysaccharide significantly decreased body weight and increased cellular T lymphocyte infiltration, caspase-3 and iNOS and decreased PPAR-γ in renal tissue. NO, creatinine and BUN were significantly elevated after LPS challenge, and they significantly decreased after GSNO treatment. TNF-α level was found significantly increased in LPS-treated serum and kidney. GSNO treatment of LPS-challenged rats decreased caspase-3, iNOS, TNF-α, T lymphocyte infiltration and remarkably increased levels of IL-10, PPAR-γ and GSH. GSNO can be used as a renoprotective agent for the treatment of sepsis-induced acute kidney injury.

Renoprotective approaches and strategies in acute kidney injury.

Acute kidney injury (AKI) is a major renal disease associated with high mortality rate and increasing prevalence. Decades of research have suggested numerous chemical and biological agents with beneficial effects in AKI. In addition, cell therapy and molecular targeting have been explored for reducing kidney tissue damage and promoting kidney repair or recovery from AKI. Mechanistically, these approaches may mitigate oxidative stress, inflammation, cell death, and mitochondrial and other organellar damage, or activate cytoprotective mechanisms such as autophagy and pro-survival factors. However, none of these findings has been successfully translated into clinical treatment of AKI. In this review, we analyze these findings and propose experimental strategies for the identification of renoprotective agents or methods with clinical potential. Moreover, we propose the consideration of combination therapy by targeting multiple targets in AKI.

Suramin Protects From Cisplatin‐Induced Acute Kidney Injury

Cisplatin, a commonly used cancer chemotherapeutic, has a dose limiting side effect of nephrotoxicity. According to the Risk, Injury, Failure, Loss of Function, and End Stage Renal Disease (RIFLE) criteria of kidney injury, approximately 30% of patients administered cisplatin suffer from kidney injury and there is currently no treatment for cisplatin‐induced kidney injury other than palliative care. Suramin, FDA‐approved for the treatment of trypanosomiasis, improves kidney function following various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin‐induced kidney injury. Suramin treatment prior to cisplatin administration reduced cisplatin‐induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin‐induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 hours after cisplatin improved kidney function, suggesting that the mechanism of protection is neither via inhibiting tubular cisplatin uptake nor its metabolism to nephrotoxic species. If suramin is to be utilized in the context of cancer, then suramin cannot prevent cisplatin‐induced cytotoxicity within tumors. Mice harboring lung adenocarcinomas were pretreated with suramin and then administered cisplatin. Lung histology and markers of kidney function indicated that suramin protected mice from cisplatin‐induced acute kidney injury, but did not inhibit cisplatin induced cytotoxic effects within the tumor. These results provide evidence that suramin has great potential as a renoprotective agent for the treatment/prevention of cisplatin‐induced acute kidney injury.Support or Funding InformationSupport for these studies was provided by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01‐ DK093462, to L.J.S]. This work was also supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01‐GM084147 to R.G.S.]; the National Institutes of Health National Center for Research Resources [Grant UL1‐RR029882 to R.G.S.]; the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [1BX000851 to R.G.S.]; the South Carolina Clinical and Translational Research Institute, with an academic home at the Medical University of South Carolina (to R.G.S.); and the National Institute of Environmental Health and Sciences (SBIR/STTR ES023767 to R.G.S.).

Estrogen attenuates renal IRI through PPAR-γ agonism in rats

BackgroundEstrogen is reported to be renoprotective agent in various preclinical studies, attributing to its antioxidant and anti-inflammatory potential. The aim of present study was to investigate the involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) in estrogen-mediated protection against renal ischemia reperfusion injury (IRI) in rats. Materials and methodsThe renal damage induced by IRI (40-min ischemia and 24-h reperfusion) was assessed by measuring serum creatinine, creatinine clearance, blood urea nitrogen, serum uric acid, electrolytes, and microproteinuria in rats. The myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. Hematoxylin-eosin and periodic acid schiff staining of renal tissues were done to demonstrate histopathologic changes. Estrogen (0.2, 0.5, and 1.0 mg/kg, i.p.) was administered 1 h before subjecting rats to renal IRI. Separately, bisphenol A diglycyl ether (BADGE, 30 mg/kg, i.p.), a PPAR-γ receptor antagonist, was given before estrogen administration followed by IRI in rats. ResultsThe ischemia reperfusion demonstrated renal damage in rats with significant changes in serum and urinary parameters, enhanced oxidative stress, and histopathologic changes in renal tissues. Estrogen administration demonstrated marked renoprotection that was attenuated by BADGE pretreatment in rats. ConclusionsIt is concluded that PPAR-γ agonism serves as one of the mechanisms in estrogen-mediated renoprotection.

Amikacin induced renal damage and the role of the antioxidants on neonatal rats

Amikacin (AK) is frequently used on the treatment of Gram-negative infections on neonates, but its usage is restricted because of nephrotoxicity. In this study, on neonatal rats, we aimed to investigate the effects of erythropoietin and vitamin E on AK induced nephrotoxicity. A total of 35 newborn Wistar Albino rats were divided into four groups: (1) injected with saline (serum physiological was administered to placebo controls), (2) injected with AK (1200 mg/kg), (3) injected with AK + vitamin E (150 mg/kg), (4) injected with AK + erythropoietin (EPO) (300 IU/kg/day). In renal tissue, AK levels were significantly high in all groups except the control. Tissue malondialdehyde (MDA) and nitric oxide (NO) levels were statistically higher in AK -treated group than the control. MDA and NO levels were significantly decreased with the administration of vitamin E and EPO. Glutathione peroxidase (GPX) levels were statistically low in AK group compared with the controls. The levels of GPX, in vitamin E group, were increased significantly. However, superoxide dismutase and catalase levels were not significantly different in none of the groups. Insulin-like growth factor-1 values in AK, EPO and vitamin E groups were significantly higher than the control group. Histomorphological changes such as tubular epithelial necrosis were seen in AK treated group. Histopathological improvements observed with EPO and vitamin E administration. AK nephrotoxicity is related to oxidative stress and is supported with biochemical and histopathological findings. Vitamin E and EPO, as antioxidants, can be useful renoprotective agents for ameliorating AK induced nephrotoxicity in neonates.

Preventive Effect of Dihydromyricetin against Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo.

Nephrotoxicity is a frequent severe side effect of cisplatin chemotherapy, limiting its clinical use despite being one of the most potent chemotherapy drugs. Dihydromyricetin is a highly abundant compound purified from the leaves of Ampelopsis grossedentata. Previous studies have demonstrated the anti-inflammatory and antioxidative effects of Dihydromyricetin both in vitro and in vivo, but little is known about the effects of Dihydromyricetin on cisplatin-induced nephrotoxicity and its underlying mechanisms. In the present study, we investigated its potential renoprotective effect and found that Dihydromyricetin ameliorated the renal functional impairment and structural damage caused by cisplatin. Moreover, Dihydromyricetin markedly attenuated cisplatin-induced oxidative stress, as well as protecting against cisplatin-induced inflammation and apoptotic cell death in mouse kidney tissues. These results collectively highlight the potential of DMY as a rational renoprotective agent against cisplatin.

Histone Lysine Methylation in TGF-β1 Mediated p21 Gene Expression in Rat Mesangial Cells.

Transforming growth factor beta1- (TGF-β1-) induced p21-dependent mesangial cell (MC) hypertrophy plays a key role in the pathogenesis of chronic renal diseases including diabetic nephropathy (DN). Increasing evidence demonstrated the role of posttranscriptional modifications (PTMs) in the event; however, the precise regulatory mechanism of histone lysine methylation remains largely unknown. Here, we examined the roles of both histone H3 lysine 4 and lysine 9 methylations (H3K4me/H3K9me) in TGF-β1 induced p21 gene expression in rat mesangial cells (RMCs). Our results indicated that TGF-β1 upregulated the expression of p21 gene in RMCs, which was positively correlated with the increased chromatin marks associated with active genes (H3K4me1/H3K4me2/H3K4me3) and negatively correlated with the decreased levels of repressive marks (H3K9me2/H3K9me3) at p21 gene promoter. TGF-β1 also elevated the recruitment of the H3K4 methyltransferase (HMT) SET7/9 to the p21 gene promoter. SET7/9 gene silencing with small interfering RNAs (siRNAs) significantly abolished the TGF-β1 induced p21 gene expression. Taken together, these results reveal the key role of histone H3Kme in TGF-β1 mediated p21 gene expression in RMC, partly through HMT SET7/9 occupancy, suggesting H3Kme and SET7/9 may be potential renoprotective agents in managing chronic renal diseases.

Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity.

Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals) to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage.

Nicorandil: What is Beyond the Anti-Anginal Action?

Page e6 Incidence of Contrast Induced Nephropathy (CIN) among ischemic heart disease patients subjected to coronary catheterization is highly dependent on the kidney function before contrast media administration and relevant risk factors, of which diabetes mellitus is the most important one.1 Incidence of CIN ranges from <2% in the general population up to 50% in patients with Advanced Kidney Disease (AKD)2 and it is the third most common cause of hospital acquired renal failure.3 Development of contrast media started by the first ionic, high-osmolar contrast agent (sodium acetrizoate) brought by Vernon Wallingford in 1953 and continued till development of the second generation non-ionic media in 1980’s.1 The exact mechanisms underlying CIN are still unclear. However, it was postulated that in addition to their direct toxic effects on renal tubular epithelial cells, contrast media trigger acute renal ischemia by inducing an imbalance between vasodilatory and vasoconstrictive factors.4 Scientific research for identification of renoprotective agents that can prevent CIN is continuously going on. No pharmacological approach has yet been shown to provide consistent protection. Furosemide, dopamine, atrial natriuretic peptide, sodium bicarbonate, sodium chloride, mannitol, endothelin receptor antagonists, ascorbic acid, fenoldopam, theophylline, N-acetylcysteine, trimetazidine and statins were all previously evaluated in prospective, randomized trials, showing positive or controversial results.5-7

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy.

Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-α) were attenuated in podocyte-specific NOX4-deficient mice. Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents.

Sildenafil obviates ischemia-reperfusion injury–induced acute kidney injury through peroxisome proliferator–activated receptor γ agonism in rats

BackgroundSildenafil is a phosphodiesterase inhibitor used clinically for treating erectile dysfunction. Few studies suggest sildenafil to be a renoprotective agent. The present study investigated the involvement of peroxisome proliferator–activated receptor γ (PPAR-γ) in sildenafil-mediated protection against ischemia-reperfusion–induced acute kidney injury (AKI) in rats. Materials and methodsThe rats were subjected to ischemia–reperfusion injury (IRI) with 40 min of bilateral renal ischemia followed by reperfusion for 24 h. The renal damage was assessed by measuring creatinine clearance, blood urea nitrogen, plasma uric acid, electrolytes, and microproteinuria in rats. The thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. The hematoxylin-eosin staining was carried out to demonstrate histopathologic changes in renal tissues. Sildenafil (0.5 and 1.0 mg/kg, intraperitoneal) was administered 1 h before subjecting the rats to renal IRI. In a separate group, bisphenol A diglycidyl ether (30 mg/kg, intraperitoneal), a PPAR-γ receptor antagonist, was given before sildenafil administration followed by IRI. ResultsThe ischemia–reperfusion demonstrated marked AKI with significant changes in serum and urinary parameters, enhanced oxidative stress, and histopathologic changes in renal tissues. The administration of sildenafil demonstrated significant protection against ischemia-reperfusion–induced AKI. The prior treatment with bisphenol A diglycidyl ether abolished sildenafil-mediated renal protection, thereby confirming involvement of PPAR-γ agonism in the sildenafil-mediated renoprotective effect. ConclusionsIt is concluded that sildenafil protects against ischemia-reperfusion–induced AKI through PPAR-γ agonism in rats.

Suramin protects from cisplatin-induced acute kidney injury.

Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer.

Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition.

Renal fibrosis is a crucial event in the pathogenesis of diabetic nephropathy (DN). The process known as epithelial to mesenchymal transition (EMT) contributes to the accumulation of matrix proteins in kidneys, in which renal tubular epithelial cells play an important role in progressive renal fibrosis. The current study investigated that chrysin (5,7-dihydroxyflavone) present in bee propolis and herbs, inhibited renal tubular EMT and tubulointerstitial fibrosis due to chronic hyperglycemia. Human renal proximal tubular epithelial cells (RPTEC) were incubated in media containing 5.5 mM glucose, 27.5 mM mannitol (as an osmotic control), or 33 mM glucose (HG) in the absence and presence of 1-20 μM chrysin for 72 h. Chrysin significantly inhibited high glucose-induced renal EMT through blocking expression of the mesenchymal markers vimentin, α-smooth muscle actin, and fibroblast-specific protein-1 in RPTEC and db/db mice. Chrysin reversed the HG-induced down-regulation of the epithelial marker E-cadherin and the HG-enhanced N-cadherin induction in RPTEC. In addition, chrysin inhibited the production of collagen IV in tubular cells and the deposition of collagen fibers in mouse kidneys. Furthermore, chrysin blocked tubular cell migration concurrent with decreasing matrix metalloproteinase-2 activity, indicating epithelial cell derangement and tubular basement membrane disruption. Chrysin restored the induction of the tight junction proteins Zona occludens protein-1 (ZO-1) and occludin downregulated in diabetic mice. Chrysin inhibited renal tubular EMT-mediated tubulointerstitial fibrosis caused by chronic hyperglycemia. Therefore, chrysin may be a potent renoprotective agent for the treatment of renal fibrosis-associated DN. • Glucose increases renal tubular epithelial induction of vimentin, α-SMA and FSP-1. • Glucose enhances renal EMT by blocking tubular epithelial E-cadherin expression. • Chrysin inhibits tubular EMT-mediated tubulointerstitial fibrosis in mouse kidneys. • Chrysin restores renal tubular induction of ZO-1 and occludin downregulated in diabetic mice. • Chrysin blocks glucose-induced renal tubular cell migration with reducing MMP-2 activity.