Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

Clinical Acute Kidney Injury and Histologic Acute Tubular-Interstitial Injury and Their Prognosis in Diabetic Nephropathy

<b><i>Introduction:</i></b> Histologic acute tubular-interstitial injury (hATI) is often observed in patients with diabetic nephropathy (DN). This study aimed to determine the relationship between hATI and clinical acute kidney injury (cAKI) and evaluate significance of hATI in patients with DN. <b><i>Methods:</i></b> Patients with biopsy-proven DN through 2003–2018 in our center were selected. The prevalence of hATI and its correlations with cAKI, tubular injury biomarkers, and serum creatinine were investigated. The renal survival rates and prognostic factors were analyzed by Kaplan-Meier curve and Cox regression model, respectively. <b><i>Results:</i></b> Of 1,414 patients with DN, 70.4% were male, with a median age of 50.0 years. The incidences of cAKI and hATI were 8.6% and 57.8%, respectively. The severities of most hATI were mild (91.0%). The incidence of cAKI in those with hATI was only 12.2%. The incidences of cAKI positively correlated with the scores of hATI (Kendall <i>r</i> = 0.273, <i>p</i> &#x3c; 0.001). The presence of hATI was related to rapid creatinine rise and increased tubular injury biomarkers although without cAKI. After adjusting for significant covariates, multivariate Cox models showed that patients with hATI alone were one and a half times more likely to develop ESRD (hazard ratio [HR]: 1.46; 95% CI, 1.05–2.02) than those without hATI or cAKI, and patients with hATI plus cAKI were 3 times more likely to develop ESRD (HR: 2.96; 95% CI, 1.85–4.72). <b><i>Conclusion:</i></b> Our findings indicated that hATI was common in patients with DN where the majorities were mild hATI and without cAKI. hATI was an independent risk factor of DN progression, regardless of episodes of cAKI.

The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response

Diabetic nephropathy (DN) is one of the most severe complications of diabetes. Inflammation mediated by inflammatory factors is thought to accelerate the progression of renal damage in DN. However, which inflammatory factors mediate the inflammatory response in DN remains unclear. In this study, we determined that the CXCL1-mediated inflammatory response may play an essential role in DN progression through bioassays. Subsequently, we observed that the expression of CXCL1 and its receptor (CXCR2) was significantly increased in the kidneys of mice with HFD + STZ induced diabetes and DN patients. In addition, inhibition of the CXCL1/CXCR2 axis by repertaxin alleviates renal inflammation and pathological damage in the kidneys of db/db mice. Finally, we noted that the CXCL1/CXCR2 axis might lead to inflammatory damage through phosphorylated NF-κB and further activate the NLRP3 inflammasome. Our results revealed the role of the CXCL1/CXCR2 axis in DN progression for the first time, which may be a novel therapeutic target for DN.

Pengaruh Pemberian Ekstrak Etanol Daun Kemangi (Ocimum basilicum L.) Terhadap Cedera Tubulus Ginjal

According to the European Food Safety Authority (EFSA),the allowed level of Monosodium glutamate (MSG)consumption is 30 mg / kgbw per day. Several studies show that long-term MSG is toxic to the kidneys bycausingoxidative stress and decreasing thekidney function.This study was based on the potential for impaired kidneyfunction and structure caused by excessive consumption of MSG and basil leaves (Ocimum basilicum L.) asantioxidant plants with flavonoid content. To find out the effect of basil (Ocimum basilicum L.) leaves’ ethanolextract dose 175 mg / kgbw, 350 mg / kgbw and 700 mg / kgbw against kidney tubular injury on white rats WistarStrain induced by MSG.This study was a quasi-experimental study with a randomized post-test only controlledgroup design. The number of samples was 25 ABM, divided into five groups, the positive control group (K+), thenegative control group (K-) and the treatment group (K1,K2 and K3).In the group given basil leaves ethanol extractdoses of 175, 350 and 700 mg / kgbw, there was a decrease in tubular injury in the kidney of the white rat (Rattusnorvegicus) Wistar strain induced by MSG 1.6 g/day orally. The optimal dose in this study was 700 mg / kgbw. Teststatistics indicated significant differences in all five groups (p < 0.05).The administration of ethanol extract of basilleaves (Ocimum basilicumL.) was able to prevent tubular injury in the kidney of the white rat (Rattus norvegicus)Wistar strain induced by MSG. Kadar konsumsi MSG yang diperbolehkan menurut Europian Food Safety Authority (EFSA) yaitu 30 mg/kgBB per hari. Beberapa studi pada hewan coba menunjukkan bahwa pemberian MSG jangka panjang bersifat toksik padaginjal dengan menyebabkan stress oksidatif dan menurunkan fungsi ginjal. Penggunaan tanaman yang mengandungantioksidan dapat meningkatkan mekanisme dalam tubuh untuk mencegah stres oksidatif. Penelitian ini didasarkanoleh potensi terjadinya gangguan fungsi dan struktur ginjal akibat stres oksidatif yang disebabkan oleh konsumsiMSG berlebih serta daun kemangi (Ocimum basilicum L.) sebagai tanaman antioksidan dengan kandunganflavonoid.Mengetahui pengaruh pemberian ekstrak etanol daun kemangi (Ocimum basilicum L.) dosis 175,350 dan700 mg/kgBB terhadap cedera tubulus pada BBT ginjal tikus putih (Rattus norvegicus) galur Wistar yang diinduksiMSG.Penelitian ini merupakan jenis penelitian quasi-experimental dengan rancangan randomized post test onlycontrolled group. Jumlah sampel sebanyak 25 BBT, terbagi menjadi lima kelompok, yaitu kontrol positif (K+),kontrol negatif (K-) dan kelompok perlakuan ekstrak daun kemangi (K1, K2 dan K3).Pada kelompok pemberianekstrak etanol daun kemangi terjadi penurunan cedera tubulus pada ginjal tikus putih (Rattus norvegicus) galur Wistar yang diinduksi MSG 1,6 g/hari secara oral. Dosis optimal ekstrak etanol daun kemangi padapenelitian iniyaitu 700 mg/kgBB. Uji statistik menuunjukkan perbedaan yang signifikan pada kelima kelompok (p<0,05). Pemberian ekstrak etanol daun kemangi (Ocimum basilicum L.) dapat mencegah terjadinya cedera tubulus padaginjal tikus putih (Rattus norvegicus) galur Wistar yang diinduksi MSG.

Renoprotective Role of Hypoxia-Inducible Factors and the Mechanism

<b><i>Background:</i></b> The kidney requires abundant blood supply, and oxygen is transmitted by diffusion through blood vessels. Most physiological metabolism of the kidney depends on oxygen, so it is very sensitive to oxygen. An increasing pool of evidence suggests that hypoxia is involved in almost all acute and chronic kidney diseases (CKDs). Vascular damage, tubular injury, and fibrosis are the main pathologies associated during hypoxia. Hypoxia-inducible factors (HIFs) are the main mediators during hypoxia, but their functions remain controversial. This article reviewed recent studies and described its mechanisms on renoprotection. <b><i>Summary:</i></b> HIF is degraded rapidly during under normal oxygen. But under hypoxia, HIFs accumulate and many target genes are regulated by HIFs. Homeostasis during injury is maintained through these genes. Pretreatment of HIF can protect the kidney from acute hypoxia and can improve repair, but HIF’s role in CKD and in renal tumor is still controversial. Due to its mechanism in kidney disease, many drugs toward HIFs are widely researched, even some of which have been used in clinical or in clinical research. <b><i>Key Messages:</i></b> In this review, we described the known physiological mechanisms, target genes, and renal protective roles of HIFs, and we discussed several drugs that are researched due to such renal protective roles.

In Vivo and In Vitro Evaluation of Urinary Biomarkers in Ischemia/Reperfusion-Induced Kidney Injury

Oxidative stress plays an important role in the pathophysiology of acute kidney injury (AKI). Previously, we reported that vanin-1, which is involved in oxidative stress, is associated with renal tubular injury. This study was aimed to determine whether urinary vanin-1 is a biomarker for the early diagnosis of AKI in two experimental models: in vivo and in vitro. In a rat model of AKI, ischemic AKI was induced in uninephrectomized rats by clamping the left renal artery for 45 min and then reperfusing the kidney. On Day 1 after renal ischemia/reperfusion (I/R), serum creatinine (SCr) in I/R rats was higher than in sham-operated rats, but this did not reach significance. Urinary N-acetyl-β-D-glucosaminidase (NAG) exhibited a significant increase but decreased on Day 2 in I/R rats. In contrast, urinary vanin-1 significantly increased on Day 1 and remained at a significant high level on Day 2 in I/R rats. Renal vanin-1 protein decreased on Days 1 and 3. In line with these findings, immunofluorescence staining demonstrated that vanin-1 was attenuated in the renal proximal tubules of I/R rats. Our in vitro results confirmed that the supernatant from HK-2 cells under hypoxia/reoxygenation included significantly higher levels of vanin-1 as well as KIM-1 and NGAL. In conclusion, our results suggest that urinary vanin-1 might be a potential novel biomarker of AKI induced by I/R.

Proximal Tubule p53 in Cold Storage/Transplantation-Associated Kidney Injury and Renal Graft Dysfunction

Kidney injury associated with cold storage/transplantation is a primary factor for delayed graft function and poor outcome of renal transplants. p53 contributes to both ischemic and nephrotoxic kidney injury, but its involvement in kidney cold storage/transplantation is unclear. Here, we report that p53 in kidney proximal tubules plays a critical role in cold storage/transplantation kidney injury and inhibition of p53 can effectively improve the histology and function of transplanted kidneys. In a mouse kidney cold storage/transplantation model, we detected p53 accumulation in proximal tubules in a cold storage time-dependent manner, which correlated with tubular injury and cell death. Pifithrin-α, a pharmacologic p53 inhibitor, could reduce acute tubular injury, apoptosis and inflammation at 24 h after cold storage/transplantation. Similar effects were shown by the ablation of p53 from proximal tubule cells. Notably, pifithrin-α also ameliorated kidney injury and improved the function of transplanted kidneys in 6 days when it became the sole life-supporting kidney in recipient mice. in vitro, cold storage followed by rewarming induced cell death in cultured proximal tubule cells, which was accompanied by p53 activation and suppressed by pifithrin-α and dominant-negative p53. Together, these results support a pathogenic role of p53 in cold storage/transplantation kidney injury and demonstrate the therapeutic potential of p53 inhibitors.