Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease (CKD) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end‐stage kidney disease (ESKD), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia‐induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia‐inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia‐induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF, TGF‐β, Notch, PKC/ERK, PI3K/Akt, NF‐κB, Ang II/ROS and microRNAs. Roles of molecules such as IL‐6, IL‐18, KIM‐1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia‐responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD.

Molybdate-based inorganic-organic hybrid disks with a highly ordered layered structure were synthesized via an acid-base reaction of white molybdic acid (MoO 3 $H 2 O) with n-octylamine (C 8 H 17 NH 2 ) in ethanol at room temperature. The thermal treatment of the as-obtained molybdatebased inorganic-organic hybrid disks at 550 C in air led to formation of orthorhombic a-MoO 3 nanoplates. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermal analysis (TG-DTA), Fourier-transform infrared (FT-IR) spectra, Raman spectra, and a laser-diffraction grain-size analyzer were used to characterize the starting materials, the intermediate hybrid precursors and the final a-MoO 3 nanoplates. The XRD, FT-IR and TG-DTA results suggested that the molybdate-based inorganic-organic hybrid compound, with a possible composition of (C 8 H 17 NH 3 ) 2 MoO 4 , was of a highly ordered lamellar structure with an interlayer distance of 2.306(1) nm, and the n-alkyl chains in the interlayer places took a double-layer arrangement with a tilt angle of 51 against the inorganic MoO 6 octahedra layers. The SEM images indicated that the molybdate-based inorganic-organic hybrids took on a well-dispersed disk-like morphology, which differed distinctly from the severely aggregated morphology of their starting MoO 3 $H 2 O powders. During the calcining process, the disk-like morphology of the hybrid compounds was well inherited into the orthorhombic a-MoO 3 nanocrystals, showing a definite plate-like shape. The a-MoO 3 nanoplates obtained were of a single-crystalline structure, with a side-length of 1-2 mm and a thickness of several nanometres, along a thickness direction of [010]. The above a-MoO 3 nanoplates were of a loose aggregating texture and high dispersibility. The chemical sensors derived from the as-obtained a-MoO 3 nanoplates showed an enhanced and selective gas-sensing performance towards ethanol vapors. The a-MoO 3 nanoplate sensors reached a high sensitivity of 44-58 for an 800 ppm ethanol vapor operating at 260-400 C, and their response times were less than 15 s.

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Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an HRE3 region on the p53 promoter as the HIF-1α-binding site. The HIF-1α‒HRE3 binding resulted in a sharp transcriptional activation of p53. Collectively, we show the presence of a hypoxia-activated, p53-responsive profibrogenic pathway in the kidney. During hypoxia, p53 upregulation induced by HIF-1αsuppresses cell cycle progression, leading to the accumulation of G2/M cells, and activates profibrotic TGF-β and CTGF-mediated signaling pathways, causing extracellular matrix production and renal fibrosis.

Acute kidney injury (AKI) is a hyper-inflammation-induced abrupt loss of kidney function and has become a major public health problem. The cecal ligation and puncture (CLP) model of peritonitis in rat pups mimics the development of sepsis-induced pediatric AKI is pre-renal without morphological changes of the kidneys and high lethality. Resveratrol, a natural polyphenolic compound with low toxicity, has obvious anti-oxidant and anti-inflammatory properties. The present study aimed to determine whether resveratrol alleviates pediatric AKI and investigated the potential mechanism. Thus, a CLP model of 17-18 day-old rat pups was used to mimic the development of sepsis-induced AKI in children. In the group treated with resveratrol, renal injury induced by CLP was alleviated with downregulation of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and kidney injury molecule (KIM)-1 expression. Nuclear factor-erythroid-2-related factor 2 (Nrf2) signaling is known to effectively inhibit inflammation, the present study found that resveratrol reduced the lipopolysaccharide-induced inflammatory response in kidney cells and induced the activation of Nrf2 signaling, including accumulation of nuclear Nrf2 and increase of the expression of Nrf2 target genes heme oxygenase (HO)-1 and NAD(P)H dehydrogenase (quinone) 1 (NQO1); this was confirmed by the induction of the expression of HO-1 and NQO1 by treatment of resveratrol and . Of note, knockdown of Nrf2 effectively abrogated the downregulation of TNF-α, IL-1β and KIM-1 expression induced by resveratrol. These results suggested that resveratrol ameliorates sepsis-induced acute kidney injury in a pediatric model of AKI via the Nrf2 signaling pathway.