Liyu He

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1.

Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

Mitochondrial Function and Disturbances in the Septic Kidney

Per milligram of tissue, only the heart exceeds the kidneys abundance of mitochondria. Not surprisingly, renal mitochondria are most densely concentrated in the epithelium of the nephron, at sites where the chemical work of moving solutes against electrochemical gradients places large and constant demands for adenosine triphosphate. Derangements of renal epithelial mitochondria appear to be a hallmark for diverse forms of acute kidney injury (AKI). The pathogenesis of multiple-organ dysfunction syndrome in sepsis is complex, but a substantial body of experimental and observational human data supports the twin concepts that mitochondrial dysfunction contributes to impaired filtration and that recovery of mitochondrial structure and function is essential for recovery from sepsis-associated AKI. These insights have suggested novel methods to diagnose, stratify, prevent, or even treat this common and deadly complication of critical illness. This review will do the following: (1) describe the structure and functions of healthy mitochondria and how renal energy metabolism relates to solute transport; (2) provide an overview of the evidence linking mitochondrial pathology to renal disease; (3) summarize the mitochondrial lesions observed in septic AKI; (4) analyze the role of mitochondrial processes including fission/fusion, mitophagy, and biogenesis in the development of septic AKI and recovery from this disease; and (5) explore the potential for therapeutically targeting mitochondria to prevent or treat septic AKI.

Mangiferin attenuate sepsis-induced acute kidney injury via antioxidant and anti-inflammatory effects.

Background: Acute kidney injury (AKI) is a frequent and serious complication of sepsis. A growing body of evidence now suggests that inflammatory reactions and tubular dysfunction induced by oxidative stress involved in the mechanisms of the disease. This study aimed to determine the role of anti-inflammatory and anti-oxidant activities of mangiferin (MA) in sepsis-induced AKI. Methods: We investigated the effects of MA on apoptosis of rat kidney proximal tubular cell (RPTC), together with renal function and morphological alterations of mice undergoing cecal-ligation and puncture (CLP). The levels of oxidative stress in kidney tissues were also determined. Moreover, we mainly focus on the effects of MA in regulating the production of NLRP3 and Nrf2 in the present study. Results: The exposure to LPS (5 Vg/ml) yielded a significant increase of apoptosis in RPTC cells, which was largely inhibited by MA pretreatment. MA attenuates renal dysfunction and ameliorates the morphological changes in the septic mice induced by CLP. MA inhibits oxidative stress, decreases serum levels of IL-1F and IL-18, and prevents tubular epithelial cells apoptosis in kidneys of CLP mice model. Data in this study also suggest that MA promotes Nrf2 expression and suppresses renal NLRP3 inflammasome activation. Conclusion: In summary, MA protects against sepsis-induced AKI through NLRP3 inflammasome inhibition and Nrf2 up-regulation. Thus, the mangiferin could thus be a promising candidate for development of a multi-potent drug. i 2014 S. Karger AG, Basel

DNA damage response in cisplatin-induced nephrotoxicity

Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and death, resulting in acute kidney injury (AKI). Recent studies have suggested that DNA damage and the associated DNA damage response (DDR) are an important pathogenic mechanism of AKI following cisplatin treatment. Activation of DDR may lead to cell cycle arrest and DNA repair for cell survival or, in the presence of severe injury, kidney cell death. Modulation of DDR may provide novel renoprotective strategies for cancer patients undergoing cisplatin chemotherapy.

Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats

BACKGROUND Gentamicin-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI). The phenotypic alterations that contribute to acute kidney injury include inflammatory response and oxidative stress. Curcumin has a wide range biological functions, especially as an antioxidant. This study was designed to evaluate the renoprotective effects of curcumin treatment in gentamicin-induced AKI. METHODS Gentamicin-induced AKI was established in female Sprague-Dawley rats. Rats were treated with curcumin (100 mg/kg body mass) by intragastric administration, once daily, followed with an intraperitoneal injection of gentamicin sulfate solution at a dose of 80 mg/kg body mass for 8 consecutive days. At days 3 and 8, the rats were sacrificed, and the kidneys and blood samples were collected for further analysis. RESULTS The animals treated with gentamicin showed marked deterioration of renal function, together with higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the plasma as compared with the controls. Animals that underwent intermittent treatment with curcumin exhibited significant improvements in renal functional parameters. We also observed that treatment with curcumin significantly attenuated renal tubular damage, apoptosis, and oxidative stress. Curcumin treatment exerted anti-apoptosis and anti-oxidative effects by up-regulating Nrf2/HO-1 and Sirt1 expression. CONCLUSIONS Our data clearly demonstrate that curcumin protects kidney from gentamicin-induced AKI via the amelioration of oxidative stress and apoptosis of renal tubular cells, thus providing hope for the amelioration of gentamicin-induced nephrotoxicity.

Renal Biopsy Findings of Patients Presenting with Isolated Hematuria: Disease Associations

Background: Most nephrologists have believed that patients with isolated hematuria (IH) generally do not require treatment and have a good prognosis. The aim of this study was to analyze the pathological characteristics and emphasize the importance of renal biopsy for patients with IH. Methods: The pathological characteristics of 90 patients with IgA nephropathy confirmed by renal biopsy and presenting with IH were reviewed. We analyzed their pathological features according to the Oxford classification by using light and immunofluorescence. Results: Total samples included 68 females and 22 males. The age of onset with IH focuses on 20–30 years. At presentation, the focal and/or segmental glomerulosclerosis (FSGS) was the most frequent diagnosis (52.22%). The distribution of hematuria focused on 20–40 thousand. 46.67% of cases had global glomerulosclerosis which excluded the physical glomerular sclerosis, and the incidence of crescent formation was 24.44%. However, the proportion of glomerular sclerosis was mainly concentrated in less than 10%. Direct immunofluorescence showed simple IgA deposition was the most common (43.33%). 46.67% of patients had accompanying complement deposition, and 92.89% had complement 3 deposition. According to the Oxford classification, M1S₀E₀T₀ accounted for 53.33%. The incidence of M, S, E, and T was 100, 30, 14.44, and 22.22% respectively. 46.67% of patients included two or more pathological lesions. Conclusions: FSGS played an important role in patients with IgA nephropathy who presented with IH. For those patients, renal biopsy was a valuable diagnostic tool and should be offered in clinical settings to provide them with maximal potential benefits.

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected. Although AKI-to-CKD transition has been intensively studied, the information of AKI on CKD is very limited. Nonetheless, AKI, when occurring in patients with CKD, is known to be more severe and difficult to recover. CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of transforming growth factor-β, p53, hypoxia-inducible factor, and major developmental pathways. At the cellular level, CKD is characterized by mitochondrial dysfunction, oxidative stress, and aberrant autophagy. At the tissue level, CKD is characterized by chronic inflammation and vascular dysfunction. These pathologic changes may contribute to the heightened sensitivity of, and nonrecovery from, AKI in patients with CKD.

TLR9 and BAFF: their expression in patients with IgA nephropathy.

Since it was first described in 1968, immunoglobulin (Ig)A nephropathy (IgAN) has become the most commonly diagnosed form of primary glomerular disease worldwide. A number of reports have shown that toll‑like receptor 9 (TLR9) and B‑cell activating factor (BAFF) may be associated with IgAN; however, sufficient evidence has not yet to be delivered. In the present study, serum levels of BAFF as well as TLR9 mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) were assessed. Expression of TLR9 mRNA in PBMCs was examined by quantitative polymerase chain reaction and the TLR9 protein was determined by western blot analysis. The levels of serum BAFF and IgA1 were determined by specific ELISA. Serum levels of BAFF and IgA1 as well as levels of TLR9 mRNA and protein in PMBCs were significantly higher in patients with IgAN compared with patients with minimal glomerular abnormalities (P<0.05, P<0.01, P<0.01 and P<0.01, respectively) and normal controls (P<0.01, P<0.01, P<0.05 and P<0.01, respectively). A correlation and regression analysis was performed to determine the pathogenesis of IgAN. In patients with IgAN, serum levels of BAFF were positively correlated with IgA1 levels (rp, 0.515; P<0.01) and mesangial IgA deposition density (rp, 0.746; P<0.01). Expression levels of TLR9 protein in PBMCs of IgAN patients were positively correlated with levels of serum BAFF (rp, 0.444; P<0.05) and IgA1 (rp, 0.633; P<0.01). These results suggested that overexpression of TLR9 mRNA and protein in PBMCs and elevated levels of serum BAFF may be associated with overexpression of serum IgA1, and, furthermore, may have a role in the development of IgAN.

PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury

ABSTRACT Damaged or dysfunctional mitochondria are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Therefore, timely removal of these organelles is critical to cellular homeostasis and viability. Mitophagy is the mechanism of selective degradation of mitochondria via autophagy. The significance of mitophagy in kidney diseases, including ischemic acute kidney injury (AKI), has yet to be established, and the involved pathway of mitophagy remains poorly understood. Here, we show that mitophagy is induced in renal proximal tubular cells in both in vitro and in vivo models of ischemic AKI. Mitophagy under these conditions is abrogated by Pink1 and Park2 deficiency, supporting a critical role of the PINK1-PARK2 pathway in tubular cell mitophagy. Moreover, ischemic AKI is aggravated in pink1 andpark2 single- as well as double-knockout mice. Mechanistically, Pink1 and Park2 deficiency enhances mitochondrial damage, reactive oxygen species production, and inflammatory response. Taken together, these results indicate that PINK1-PARK2-mediated mitophagy plays an important role in mitochondrial quality control, tubular cell survival, and renal function during AKI.

Astaxanthin Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis

Background/Aim: Focal segmental glomerulosclerosis (FSGS) is a specific pattern of chronic renal injury with progressive glomerular scarring. The phenotypic alterations that contribute to FSGS include inflammatory response and oxidative stress. Astaxanthin (ATX) has a broad range of biological functions, particularly antioxidant and anti-inflammatory ones. This study was designed to evaluate the renoprotective effect of ATX treatment on Adriamycin-induced FSGS. Methods: In Balb/c mice, Adriamycin nephropathy was induced by Adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then the mice were treated with ATX (50 mg/kg body weight) once daily by oral gavage, again starting on the day of Adriamycin injection and continued for 6 weeks. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. Results: Animals that underwent intermittent exposure to ATX treatment exhibited significant improvements in renal functional parameters as well as in glomerular and interstitial fibrosis compared to those undergoing saline treatment in FSGS mouse models. ATX treatment exerted anti-inflammatory and antioxidant effects by promoting Nrf2 expression and suppressing renal nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome activation. Conclusion: ATX might offer a ray of hope for ameliorating FSGS.