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(1) Background: 12-lipoxygenase (12-LO) is involved in the development of diabetic nephropathy (DN). In the present study, we investigated whether 12-LO inhibition may ameliorate type-2 DN (T2DN) by interfering with insulin resistance (IR); (2) Methods: Rat glomerular mesangial cells, glomeruli and skeletal muscles were isolated and used in this study. Kidney histological changes were confirmed by periodic-acid Schiff staining; mRNA expression was detected by competitive reverse transcription polymerase chain reaction; and the protein level was determined by Western blot and the enzyme-linked immunosorbent assay, respectively; (3) Results: The inhibition of 12-LO attenuated microalbuminuria (MAU) increases in type-2 diabetic rats, but not in type-1 diabetic rats. Infusion of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) significantly increased the expression of angiotensin II (Ang II) and Ang II type 1 receptor (AT1R), but decreased the expression of AT1R-associated protein (ATRAP) in rat glomeruli, compared to the control. An in vitro study revealed that both 12(S)-HETE and insulin upregulated AT1R expression in rat mesangial cells. In the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, the 12(S)-HETE-induced ATRAP reduction was significantly abolished. Interestingly, 12-LO inhibition did not influence AT1R expression in type-1 diabetic rats, but significantly abolished the increased AT1R and Ang II expression in glomeruli of type-2 diabetic rats. Furthermore, the inhibition of 12-LO significantly corrected impaired insulin sensitivity and fast serum insulin level, as well as the p-AMP-activated protein kinase (AMPK) reduction in skeletal muscle of type-2 diabetic rats; (4) Conclusion: The inhibition of 12-LO potentially ameliorated MAU by preventing IR through the downregulation of glomerular AT1R expression in T2DN.

Background/Aims: Arachidonic acid-metabolizing enzyme, 12-lipoxygenase (12-LO), is involved in the glomerular hypertrophy of diabetic nephropathy (DN), in which cyclin-dependent kinase inhibitors (CKIs) play important roles. However, it is unclear whether 12-LO regulates the expression of the CKI p16^ink4a in DN. Methods: Primary glomerular mesangial cells (MCs) and glomeruli isolated from rats were used in this study. The rats were fed a high-fat diet and given low-dose streptozotocin to induce type 2 diabetes. The 12-LO product, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), was infused through an osmotic minipump. Enzyme-linked immunosorbent assay, Western blot, and morphometric analyses were performed. Results: High glucose (HG) increased the p16^ink4a protein expression in MCs, but this increase was prevented by the 12-LO inhibitor, cinnamyl-3,​4-dihydroxy-α-cynanocinnamate (CDC). The levels of p-p38MAPK and p16^ink4a in MCs were significantly elevated after the 12(S)-HETE treatment, whereas the p38MAPK inhibitor SB203580 prevented these increases. Compared with levels in control MCs, marked increases in p38MAPK activation and p16^ink4a expression were observed in MCs plated on collagen IV, while the CDC treatment prevented these changes. Subcutaneous injection of CDC did not affect glucose levels, but completely attenuated the diabetes-related increases in the 12(S)-HETE content, p16^ink4a expression, p-p38MAPK levels, glomerular volume, and the kidney/body weight ratio. Compared with levels in controls, p16^ink4a and p-p38MAPK in the glomeruli derived from 12(S)-HETE-treated rats were significantly higher. Conclusions: 12-LO-p38MAPK mediates the upregulation of p16^ink4a in HG-stimulated MCs and type 2-diabetic glomeruli, and new therapies aimed at 12-LO inhibition may prove beneficial in ameliorating diabetes-induced glomerular hypertrophy.

Purpose: This meta-analysis aimed to determine the diagnostic performance of neutrophil gelatinase-associated lipocalin (NGAL) in diabetic nephropathy (DN). Methods: We searched the PubMed, Embase, Wanfang, and China National Knowledge Infrastructure databases for articles published up to 24 April 2019. The meta-analyses were conducted by Stata 11.0, and diagnostic accuracy, sensitivity, specificity, negative and positive likelihood ratios (NLR and PLR), diagnostic odds ratio (DOR), and receiver operating characteristic (ROC) curve data were pooled. Moreover, heterogeneity and small trials bias were evaluated. Results: Six cross-sectional studies were included in the meta-analysis. For the studies of microalbuminuria versus normoalbuminuria, the estimates (95% confidence interval) were as follows: sensitivity, 0.75 (0.51–0.89); specificity, 0.78 (0.70–0.84); PLR, 3.37 (2.49–4.56); NLR, 0.33 (0.16–0.69); DOR, 10.31 (4.05–26.25); and area under the ROC curve (AUC), 0.81 (0.77–0.84). For the studies of microalbuminuria + macroalbuminuria versus normoalbuminuria, the results were as follows: sensitivity, 0.83 (0.66–0.93); specificity, 0.88 (0.67–0.97); PLR, 7.20 (1.97–26.31); NLR, 0.19 (0.08–0.46); DOR, 37.83 (4.84–295.65); AUC, 0.92 (0.90–0.94). Deeks’ funnel plot suggested that small trials bias was insignificant in this study. Conclusions: Our findings suggest that NGAL is a potential diagnostic marker for patients with DN and that its diagnostic value for microalbuminuria + macroalbuminuria is superior to that for microalbuminuria. Highlights The first meta-analysis to investigate NGAL diagnostic role in DN. NGAL is valuable for the early diagnosis of DN. The diagnostic value of NGAL in microalbuminuria + macroalbuminuria was much higher.

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