Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy.

Tubulointerstitial inflammation plays an important role in the progression of diabetic nephropathy (DN), and tubular epithelial cells (TECs) are crucial promoters of the inflammatory cascade. Exchange protein activated by cAMP (Epac) has been shown to suppress the angiotensin II (Ang-II)-induced release of inflammatory cytokines in tubular cells. However, the role of Epac in TEC-mediated tubulointerstitial inflammation in DN remains unknown. We found that administering the Epac agonist 8-pCPT-2'-O-Me-cAMP (8-O-cAMP) to db/db mice inhibited tubulointerstitial inflammation characterized by macrophage infiltration and increased inflammatory cytokine release and consequently alleviated tubulointerstitial fibrosis in the kidney. Furthermore, 8-O-cAMP administration restored CCAAT/enhancer binding protein ß (C/EBP-ß) expression and further upregulated the expression of Suppressor of cytokine signaling 3 (SOCS3), while inhibiting p-STAT3, MCP-1, IL-6, and TNF-α expression in the kidney cortex in db/db mice. And in vitro study showed that macrophage migration and MCP-1 expression induced by high glucose (HG, 30 mM) were notably reduced by 8-O-cAMP in human renal proximal tubule epithelial (HK-2) cells. In addition, 8-O-cAMP treatment restored C/EBP-ß expression in HK-2 cells and promoted C/EBP-ß translocation to the nucleus, where it transcriptionally upregulated SOCS3 expression, subsequently inhibiting STAT3 phosphorylation. Under HG conditions, siRNA-mediated knockdown of C/EBP-ß or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on the release of MCP-1. In contrast, SOCS3 overexpression inhibited HG-induced activation of STAT3 and MCP-1 expression in HK-2 cells. These findings indicate that Epac activation via 8-O-cAMP ameliorates tubulointerstitial inflammation in DN through the C/EBP-ß/SOCS3/STAT3 pathway.

Nocardiosis in glomerular disease patients with immunosuppressive therapy.

BACKGROUND: Glomerular disease patients have a high risk of infection, which contributes to the progression of disease per se and mortality, especially in those with long-term use of glucocorticoids and (or) immunosuppressive agents. Cases of sporadic nocardiosis have been reported in glomerular disease patients, and this observation was conducted to comprehensively understand the manifestations of and treatments for nocardiosis, which is commonly misdiagnosed as pneumonia or tuberculosis or even as lung cancer or metastatic tumors in glomerular disease patients. METHODS: We reviewed the demographic characteristics, laboratory abnormalities, radiological features, and treatments of 7 patients with nocardiosis and glomerular disease receiving steroids and immunosuppression therapy at the nephrology department of the Second Xiangya Hospital between 2012 and 2019. RESULTS: It was found that all 7 patients had been receiving methylprednisolone for renal disease at a median dose of 20 mg per day and a median duration of 4 months before developing nocardiosis. There were 4 males and 3 females, and the median age was 52.14 years. All 7 patients had hypoalbuminemia at the time of admission. In addition, various cystic abscesses in the subcutaneous tissue, with or without lung and brain involvement, were observed in these patients. Encouragingly, body temperatures returned to normal, and subcutaneous abscesses diminished or disappeared with compound sulfamethoxazole treatment alone or in combination with linezolid, imipenem and mezlocillin/sulbactam. CONCLUSIONS: It was shown that multisite abscesses, including subcutaneous, pulmonary and cerebral abscesses, were the common manifestations of nocardiosis in glomerular disease patients. Sulfonamide was the first-line antibiotic therapy for nocardiosis, and combinations of other antibiotics were also needed in some serious cases.

Tacrolimus ameliorates tubulointerstitial inflammation in diabetic nephropathy via inhibiting the NFATc1/TRPC6 pathway.

Tubulointerstitial inflammation is crucial for the progression of diabetic nephropathy (DN), and tubular cells act as a driving force in the inflammatory cascade. Emerging data suggested that tacrolimus (TAC) ameliorates podocyte injury and macrophage infiltration in streptozotocin (STZ) mice. However, the effect of TAC on tubulointerstitial inflammation remains unknown. We found that albuminuria and tubulointerstitial damage improved in db/db mice treated with TAC. Macrophage infiltration and expression of IL-6, TNF-α, fibronectin, collagen 1 and cleaved caspase 3 were inhibited as well. In addition, the expression of nuclear factor of activated T cell 1 (NFATc1) and transient receptor potential channel 6 (TRPC6) was up-regulated in the kidneys of DN patients and correlated with tubular injury and inflammation. The expression of NFATc1 and TRPC6 also increased in the kidneys of db/db mice and HK-2 cells with high glucose (HG), while TAC inhibited these effects. HG-induced inflammatory markers and apoptosis were reversed by TAC and NFATc1 siRNA in HK-2 cells, which was abolished by TRPC6 plasmid. Furthermore, HG-induced TRPC6 expression was inhibited by NFATc1 siRNA, while NFATc1 nuclear translocation was inhibited by TAC, but was restored by TRPC6 plasmid in HK-2 cells under HG conditions. These findings suggest that TAC ameliorates tubulointerstitial inflammation in DN through NFATc1/TRPC6 feedback loop.

Sinocyclocheilus sanxiaensis, a new blind fish from the Three Gorges of Yangtze River provides insights into speciation of Chinese cavefish.

A blind fish of Sinocyclocheilus (Cypriniformes: Cyprinidae) was caught in open water in the Three Gorges (Sanxia) reservoir, at a depth of 20 m in the mainstream of Yangtze River in Zigui County, Hubei Province, China. This fish can be easily distinguished from all other congeners by external morphological characteristics, and is estimated to have diverged from its sister group about 0.55 million years ago (Ma). The geologically well separated locality of this species has expanded the distribution of Sinocyclocheilus cavefish from around N25°(latitude) to above N30°. Herein, we describe this new species as Sinocyclocheilus sanxiaensis sp. nov., and discuss the possible reasons why the species appears, surprisingly, in the Three Gorges reservoir.

Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease.

Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes II-III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl-ß-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-α (TNF-α) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-α levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-α expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD.