Previous studies of Jak–STAT inhibitors have shown promise in treating kidney diseases. The activation of Jak–STAT components is important in cell fate determination in many cell types, including bone marrow–derived cells, which are important contributors in renal interstitial fibrosis. In this study, we tested the effect of a new STAT3 inhibitor, BP-1-102, on monocyte-to-fibrocyte transition and the progression of renal interstitial fibrosis. We tested the effect of BP-1-102 in a mouse model of unilateral ureteral obstruction in vivo and IL-33-treated bone marrow–derived monocytes in vitro. BP-1-102 treatment alleviated renal interstitial fibrosis, reduced collagen deposition and extracellular matrix protein production, inhibited inflammatory cell infiltration, suppressed the percentage of CD45+ PDGFRβ+, CD45+ CD34− Col I+ and CD45+ CD11b+ Col I+ cells within the obstructed kidney and reduced the mRNA levels of the proinflammatory and profibrotic cytokines IL-1β, TGF-β, TNF-α, ICAM-1, and CXCL16. In vitro, BP-1-102 inhibited the IL-33–induced phenotypic transition into fibroblast precursors in bone marrow–derived monocytes, marked by reduced CD45+ CD34− Col I+ and CD45+ CD11b+ Col I+ cell percentage. Our results indicate a potential mechanism by which the STAT3 inhibitor BP-1-102 inhibits bone marrow–derived monocyte transition into fibroblast precursors in an IL-33/STAT3–dependent manner and thereby alleviates renal interstitial fibrosis.

Fibrosis is defined as an excessive deposition of extracellular matrix (ECM), which leads to the destruction of organ structure and impairment of organ function. Fibrosis occurs not only in kidney but also in lung, liver, heart, and skin. Common pathways of fibrosis are thought to exist. Renal interstitial fibrosis is a complex process that involves multiple molecular signaling and multiple cellular components, in which B cells appear to be one of the emerging important players. B cells may affect fibrosis through cytokine production and through interaction with other cells including fibroblasts, macrophages and T cells. This review summarizes recent research findings of B cells in fibrosis and provides an insight of how the future therapeutics of fibrosis could be developed from a B‐cell point of view.

Background: Minimal change nephropathy (MCD) is a common pathological type of nephrotic syndrome and is often associated with acute kidney injury (AKI). This study aimed to investigate the clinical characteristics and related factors of AKI in patients with MCD and nephrotic syndrome. Methods: Patients from Chinese People's Liberation Army General Hospital who were diagnosed with pathological renal MCD with clinical manifestations of nephrotic syndrome were included from January 1, 2013 to December 31, 2017. Patients diagnosed with membranous nephropathy (MN) by renal biopsy from January 1, 2013 to December 31, 2017 are included as a control population. We retrospectively analyzed the clinical and pathological characteristics of patients as well as the percentages and clinical characteristics of AKI in different age groups. We assessed the correlation of pathological characteristics with serum creatinine using multivariate linear regression analysis. Results: A total of 367 patients with MCD were included in the analysis, with a sex ratio of 1.46: 1 (male: female) and an age range of 6 to 77 years. Among all the patients, 109 developed AKI (29.7%), and of these patients, 85 were male (78.0%). In the 586 patients with MN, 27 (4.6%) patients developed AKI. The percentage of AKI in MCD patients was significantly higher than that in MN patients ( χ 2 = 41.063, P < 0.001). The percentage of AKI increased with age in the MCD patients. The percentage of AKI in patients aged 50 years or older was 52.9% (46/87), which was significantly higher than that [22.5% (63/280)] in patients under 50 years ( χ 2 = 6.347, P = 0.013). We observed statistically significant differences in age (43 [27, 59] years vs. 28 [20, 44] years, Z = 5.487, P < 0.001), male (78.0% vs . 51.4%, χ 2 = 22.470, P < 0.001), serum albumin (19.9 ± 6.1 g/L vs. 21.5 ± 5.7 g/L, t = 2.376, P = 0.018), serum creatinine (129.5 [105.7, 171.1] μmol/L vs. 69.7 [57.7, 81.9] μmol/L, Z = 14.190, P < 0.001), serum urea (10.1 [6.2, 15.8] mmol/L vs. 4.7 [3.6, 6.4] mmol/L, Z = 10.545, P < 0.001), IgE (266.0 [86.7, 963.0] IU/ml vs . 142.0 [35.3, 516.5] IU/ml, Z = 2.742, P = 0.007), history of diabetes (6.4% vs. 1.2%, P = 0.009), and history of hypertension (23.9% vs. 5.1%, χ ...

Two studies have concluded that lithium exposure extends the lifespan of Caenorhabditis elegans. However, the effect of lithium on another widely used model organism, Drosophila melanogaster, remains unclear. Here, we demonstrate that chronic treatment with a low to moderate dose of lithium chloride does not extend lifespan in D. melanogaster and that the drug abolishes the female lifespan advantage in flies.

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Mesangial cell (MC) proliferation is a key pathological feature in a number of common human renal diseases, including mesangial proliferative nephritis and diabetic nephropathies. Knowledge of MC responses to pathological stimuli is crucial to the understanding of these disease processes. We previously determined that Krϋppel‐like factor 15 (KLF15), a kidney‐enriched zinc‐finger transcription factor, was required for inhibition of MC proliferation. In the present study, we investigated the direct target gene and the underlying mechanism by which KLF15 regulated mesangial proliferation. First, we screened small ubiquitin‐related modifier 1 (SUMO1) as the direct transcriptional target of KLF15 and validated this finding with ChIP‐PCR and luciferase assays. Furthermore, we demonstrated that overexpressing KLF15 or SUMO1 enhanced the stability of P53, which blocked the cell cycle of human renal MCs (HRMCs) and therefore abolished cell proliferation. Conversely, knockdown of SUMO1 in HRMCs, even those overexpressed with KLF15, could not inhibit HRMC proliferation rates and increase SUMOylation of P53. Finally, the results showed that the levels of SUMOylated P53 in the kidney cortices of anti‐Thy 1 model rats were decreased during proliferation periods. These findings reveal the critical mechanism by which KLF15 targets SUMO1 to mediate the proliferation of MCs.

Background Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes. Methods Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration. Results An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition. Conclusions The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

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