Macrophage autophagy protects against acute kidney injury by inhibiting renal inflammation through the degradation of TARM1.

Macroautophagy/autophagy activation in renal tubular epithelial cells protects against acute kidney injury (AKI). However, the role of immune cell autophagy, such as that involving macrophages, in AKI remains unclear. In this study, we discovered that macrophage autophagy was an adaptive response during AKI as mice with macrophage-specific autophagy deficiency (atg5-/-) exhibited higher serum creatinine, more severe renal tubule injury, increased infiltration of ADGRE1/F4/80+ macrophages, and elevated expression of inflammatory factors compared to WT mice during AKI induced by either LPS or unilateral ischemia-reperfusion. This was further supported by adoptive transfer of atg5-/- macrophages, but not WT macrophages, to cause more severe AKI in clodronate liposomes-induced macrophage depletion mice. Similar results were also obtained in vitro that bone marrow-derived macrophages (BMDMs) lacking Atg5 largely increased pro-inflammatory cytokine expression in response to LPS and IFNG. Mechanistically, we uncovered that atg5 deletion significantly upregulated the protein expression of TARM1 (T cell-interacting, activating receptor on myeloid cells 1), whereas inhibition of TARM1 suppressed LPS- and IFNG-induced inflammatory responses in atg5-/- RAW 264.7 macrophages. The E3 ubiquitin ligases MARCHF1 and MARCHF8 ubiquitinated TARM1 and promoted its degradation in an autophagy-dependent manner, whereas silencing or mutation of the functional domains of MARCHF1 and MARCHF8 abolished TARM1 degradation. Furthermore, we found that ubiquitinated TARM1 was internalized from plasma membrane into endosomes, and then recruited by the ubiquitin-binding autophagy receptors TAX1BP1 and SQSTM1 into the autophagy-lysosome pathway for degradation. In conclusion, macrophage autophagy protects against AKI by inhibiting renal inflammation through the MARCHF1- and MARCHF8-mediated degradation of TARM1.Abbreviations: AKI, acute kidney injury; ATG, autophagy related; Baf, bafilomycin A1; BMDMs, bone marrow-derived macrophages; CCL2/MCP-1, C-C motif chemokine ligand 2; CHX, cycloheximide; CQ, chloroquine; IFNG, interferon gamma; IL, interleukin; IR, ischemia-reperfusion; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MARCHF, membrane associated ring-CH-type finger; NC, negative control; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3, NLR family, pyrin domain containing 3; NOS2, nitric oxide synthase 2, inducible; Rap, rapamycin; Wort, wortmannin; RT-qPCR, real-time quantitative polymerase chain reaction; Scr, serum creatinine; SEM, standard error of mean; siRNA, small interfering RNA; SYK, spleen tyrosine kinase; TARM1, T cell-interacting, activating receptor on myeloid cells 1; TAX1BP1, Tax1 (human T cell leukemia virus type I) binding protein 1; TECs, tubule epithelial cells; TNF, tumor necrosis factor; WT, wild type.

Research Progress of Drug Delivery Systems Targeting the Kidneys.

Chronic kidney disease (CKD) affects more than 10% of the global population, and its incidence is increasing, partially due to an increase in the prevalence of disease risk factors. Acute kidney injury (AKI) is an independent risk factor for CKD and end-stage renal disease (ESRD). The pathogenic mechanisms of CKD provide several potential targets for its treatment. However, due to off-target effects, conventional drugs for CKD typically require high doses to achieve adequate therapeutic effects, leading to long-term organ toxicity. Therefore, ideal treatments that completely cure the different types of kidney disease are rarely available. Several approaches for the drug targeting of the kidneys have been explored in drug delivery system research. Nanotechnology-based drug delivery systems have multiple merits, including good biocompatibility, suitable degradability, the ability to target lesion sites, and fewer non-specific systemic effects. In this review, the development, potential, and limitations of low-molecular-weight protein-lysozymes, polymer nanomaterials, and lipid-based nanocarriers as drug delivery platforms for treating AKI and CKD are summarized.

Effect of river-lake connectivity on ecological stoichiometry of lake and carbon storage status in Eastern Plain, China.

C, N, and P in lake sediment are the basis of material and energy cycle, reflecting the economic development, ecological function, and environmental effect. Current research on the effect of lake eutrophication on carbon storage and the river-lake connectivity on nutrient diffusion is lack. This work investigated the accumulation, distribution, correlations, and stoichiometric ratios of C, N, and P of 82 lakes (≥ 10 km2) in Eastern China, analyzed the nutrient limitation, sediment carbon sink, and effect of river-lake connectivity, and discussed the relationships between eutrophication and sediment carbon storage. The average concentrations and ranges of total C, N, and P in lake sediments were (23.26 mg/g, 0.08-153.45 mg/g), (2.32 mg/g, 0.29-14.17 mg/g), and (0.86 mg/g, 0.23-2.64 mg/g), respectively. The ecological stoichiometry of C: N: P in lake sediments was 32: 3.2: 1. P can be easily accumulated in lakes connected from the Yangtze River, while C and N can be easily accumulated in disconnected lakes. The soil-water erosion in runoff is an important factor for P diffusion. The C/N and C/N/P weren't affected by the river-lake connectivity but depended on the plant type. The Eastern Plain Lake Region of China is C and N co-depletion, and P enrichment. The lake eutrophication leading to algal bloom is unfavorable to the goal of carbon storage and carbon neutrality. Outcome of this study will provide a significant reference and strategies for carbon sequestration research, eco-environmental protection, and watershed nutrient management.

Effect of river-lake connectivity on heavy metal diffusion and source identification of heavy metals in the middle and lower reaches of the Yangtze River.

Metal pollution poses a significant threat to ecological security and human health. Current research on the causes, sources and distribution of metal pollution in the Yangtze River plain is lacking. This study investigated the accumulation, risk, distribution, and sources of heavy metals in 62 lakes along the Yangtze River, and analyzed the relationship between river-lake connectivity, economic structure, population and metal diffusion. The mean concentrations of Cr, Cu, Hg, Zn, Cd, Pb and As in the surface sediments of these lakes were 90.8, 60.1, 0.06, 102, 0.89, 42.7, and 6.01 mg/kg, respectively. Most (99%) of the lake sediments were contaminated with Cd, and the lakes in the middle reach and southern bank of the Yangtze River had a higher ecological risk. Cr originated from the natural environment, whereas Zn, Cu, Pb, Cd and As were affected by human activities. The lakes disconnected from the Yangtze River had higher concentrations of Cu, Zn, Pb and As, while the lakes connected to the river had higher concentrations of Cd and Cr. This comprehensive analysis determined the pollution characteristics of heavy metals, illustrated the causes of non-point pollution in the Yangtze River plain, and showed that soil-water erosion is important in metal diffusion.