Combined Plasma Olink Proteomics and Transcriptomics Identifies CXCL1 and TNFRSF12A as Potential Predictive and Diagnostic Inflammatory Markers for Acute Kidney Injury.

Acute kidney injury (AKI) poses a significant global public health challenge. Current methods for detecting AKI rely on monitoring changes in serum creatinine (Scr), blood urea nitrogen (BUN), urinary output and some commonly employed biomarkers. However, these indicators are usually neither specific nor sensitive to AKI, especially in cases of mild kidney injury. AKI is accompanied by severe inflammatory reactions, resulting in the upregulation of numerous inflammation-associated proteins in the plasma. Plasma biomarkers are a noninvasive method for detecting kidney injury, and to date, plasma inflammation-associated cytokines have not been adequately studied in AKI patients. The objective of our research was to identify novel inflammatory biomarkers for AKI. We utilized Olink proteomics to analyze the alterations in plasma inflammation-related proteins in the serum of healthy mice (n = 2) or mice treated with cisplatin (n = 6). Additionally, transcriptome datasets for the lipopolysaccharide (LPS), cisplatin, and ischemia‒reperfusion injury (IRI) groups were obtained from the National Center of Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We calculated the intersection of differentially expressed proteins (DEPs) and genes (DEGs) from both datasets. In the Olink proteomics analysis, the AKI group had significantly greater levels of 11 DEPs than did the control group. In addition, 56 common upregulated DEGs were obtained from the transcriptome dataset. The expression of CXCL1 and TNFRSF12A overlapped across all the datasets. The transcription and protein expression levels of CXCL1 and TNFRSF12A were detected in vivo. The gene and protein levels of CXCL1 and TNFRSF12A were significantly increased in different AKI mouse models and clinical patients, suggesting that these genes and proteins could be potential specific biomarkers for the identification of AKI.

Trametenolic Acid Ameliorates the Progression of Diabetic Nephropathy in db/db Mice via Nrf2/HO-1 and NF-κB-Mediated Pathways.

Diabetic nephropathy (DN) is a fatal complication of diabetes and the main cause of end-stage renal disease. Due to the suboptimal effects of current treatments, there is an urgent need to develop new therapeutic strategies for DN. Trametenolic acid (TA), a lanostane-type tetracyclic triterpenoid, is one of the main active ingredients extracted from the natural product Inonotus obliquus. Our study was aimed at clarifying the potential protective effects of TA on DN and its underlying mechanism. In this research, C57BLKS/db (db/db) mice were used as the spontaneous DN model, and TA (10 mg/kg/d) was intraperitoneally injected for 4 consecutive weeks. Ratio of right kidney weight/body weight was calculated, and the contents of serum creatinine (Scr), blood urea nitrogen (BUN), and urine albumin were detected. The activities of superoxide dismutase (SOD) and catalase (CAT) and the contents of reductive glutathione (GSH) and malondialdehyde (MDA) were measured. The histopathological changes of renal tissues were observed by hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson staining. The protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO-1), nuclear factor kappa B (NF-κB), proinflammation cytokine tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), Nephrin, and Podocin were detected by western blot assay. Immunohistochemistry was utilized to detect expressions of collagen III (COL-III) and fibronectin (FN). Our results showed that TA administration significantly reduced the ratio of right kidney weight/body weight, BUN, Scr, and urine albumin levels and alleviated the histopathological changes of DN mice. Moreover, TA administration remarkably increased GSH content and SOD and CAT activities and decreased MDA content. Western blot assay demonstrated that TA activated Nrf2 signaling and increased the expression of downstream antioxidant enzymes HO-1 and NQO-1. Further studies illustrated that NF-κB signaling was inhibited, and downstream proinflammation cytokine expressions of TNF-α, IL-6, and IL-1ß were also downregulated. In addition, we also found that TA administration significantly increased the expression of nephrin and podocin proteins and reduced the protein expression of COL-III and FN. These findings suggested that TA exhibited a renoprotective effect by ameliorating oxidative stress and inflammation via Nrf2/HO-1 and NF-κB signaling pathways.