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// Da-Peng Chen 1, 2, * , Ye-Ping Ma 1, 2, * , Li Zhuo 2 , Zheng Zhang 1, 2 , Gu-Ming Zou 2 , Yue Yang 2 , Hong-Mei Gao 2 and Wen-Ge Li 1, 2 1 Graduate School of Peking Union Medical College, Beijing 100730, China 2 Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China * These authors share co-first authorship Correspondence to: Wen-Ge Li, email: wenge_lee2002@126.com Keywords: diabetic nephropathy; 1,25-Dihydroxyvitamin D 3 ; proliferation; DDIT4; mTOR Received: July 31, 2017 Accepted: November 14, 2017 Published: December 09, 2017 ABSTRACT 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH) 2 D 3 could inhibit the proliferation of rat mesangial cells exposed to high glucose via the DNA-damage-inducible transcript 4/mammalian target of rapamycin(DDIT4/mTOR) pathway. The cell proliferation rate and cell cycle duration were measured using cell counting kit-8 assay and flow cytometry. Protein expression was assayed by Western blot. Glucose acted as a growth factor in rat mesangial cells, promoted cell proliferation. In parallel, the protein expression of DDIT4, TSC1/TSC2, and 4E-BP1 were decreased, and Rheb, mTOR, and p70S6K were increased. Acting via the DDIT4/mTOR signaling, 1,25(OH) 2 D 3 treatment reversed these pathological changes, upregulated DDIT4, TSC1/TSC2, and 4E-BP1, downregulated Rheb, mTOR, and p70S6K. The short-term overexpression of DDIT4 inhibited the proliferation of rat mesangial cells, similar to 1,25(OH) 2 D 3 treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH) 2 D 3 . These results suggest that 1,25(OH) 2 D 3 inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mTOR signaling pathway.

Introduction:The aims of this study were to assess the renal expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor in human type 2 diabetic nephropathy (DN).Materials and methods:In total, 115 patients diagnosed with DN by renal biopsy were enrolled in this study. The protein expression levels of the AT1R, AT2R, and MAS receptors were assessed by immunohistochemistry.Results:The protein expression levels of AT1R, AT2R, and MAS receptor in the renal biopsy tissue were correlated with the pathologic classification of DN. Tubulointerstitial AT1R expression in patients of class IIb was significantly stronger than control samples ( p < 0.05). Expression of AT2R and MAS receptors were highest with class IIb DN patients. When DN patients were treated with AT1R blocker (ARB), the expression of AT1R was downregulated ( p < 0.05), and the MAS receptor was upregulated in tubular interstitial ( p < 0.05).Conclusions:Our results directly observed that renal expression levels of AT1R increase during the early stages of DN, ARB reducing AT1R while increasing MAS receptor. Therefore, ARB should be used as soon as possible in patients with DN.

The critical role of the intrarenal renin-angiotensin system (RAS) in the development of kidney disease has been well demonstrated in animal and cell-culture experiments, but evidence from human kidney tissues is lacking. In this study, we screened 438 patients with IgA nephropathy (IgAN) and analyzed their clinical characteristics. Renal biopsy revealed the expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor (MASR) in the tissues of 260 patients not treated with RAS inhibitors, 32 patients treated with angiotensin-converting enzyme inhibitors (ACEIs), and 89 patients treated with angiotensin receptor blockers (ARBs). The correlations in expression among these three receptors and the results of Oxford typing were analyzed, together with the ability of ACEIs and ARBs to reduce proteinuria and the effects of ARBs on AT1R and AT2R expression. The results showed significantly higher AT1R, AT2R, and MASR expression in the M1 group (mesangial score 0.5) than in the M0 group (mesangial score 0.5), significantly higher AT1R expression in the S1 group (presence of segmental glomerulosclerosis) than in the S0 group (absence of segmental glomerulosclerosis); AT1R expression in the C2 group (crescent formation 25%) was significantly higher than in the C0 (crescent formation = 0) and C1 (crescent formation 25%) groups. Patients treated with an ARB for 6 months had significantly lower urinary protein levels than those taking these drugs for 6 months. These findings imply that overexpression of AT1R on the mesangial cells of IgAN patients is associated with mesangial cell proliferation, glomerular segmental sclerosis, and crescent formation. In addition, long-term administration of ARB may decrease the efficacy of these medications in terms of reducing proteinuria.

Objective Rheum officinale is a traditional medicinal herb used widely in China to treat chronic renal failure, but the proof of evidence-based medicine is poor. This meta-analysis aims to assess the benefits of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) supplemented with Rheum officinale for delaying the progression of chronic renal failure. Materials and methods The MEDLINE, EMBASE, Cochrane Library, SinoMed, Chinese National Knowledge Infrastructure, Wanfang, and VIP databases were searched to identify studies published before September 2016 that investigated the effects of ACEI/ARB plus the Chinese patented medicine Rheum (CPM-Rheum) compared to ACEI/ARB alone in lowering serum creatinine (SCr) and blood urea nitrogen (BUN) levels in chronic renal failure patients. Review Manager 5.3 was used to perform the meta-analysis. Fixed- and random-effects models were used to analyze the data. Results The meta-analysis included nine clinical trials. Comparisons of patients before and after treatment with ACEI/ARB plus CPM-Rheum or ACEI/ARB alone revealed that ACEI/ARB plus CPM-Rheum resulted in significantly greater reductions in SCr (short-term: weighted mean difference (WMD): 17.26, 95% confidence interval (CI): 7.28 - 27.24; long-term: WMD: 63.71, 95% CI: 51.01 - 76.41) and BUN (short-term: WMD: 1.70, 95% CI: 1.27 - 2.12; long-term: WMD: 3.98, 95% CI: 3.14 - 4.82) than ACEI/ARB alone. Conclusion In patients with chronic renal failure, the addition of CPM-Rheum to ACEI/ARB significantly lowered both SCr and BUN, particularly after long-term administration. Thus, the combination of ACEI/ARB and CPM-Rheum may improve the treatment of patients with impaired renal function. .

Hepatitis B virus-associated membranous nephropathy (HBV-MN) is the most common renal extra-hepatic manifestation in patients with chronic HBV infection. In September 2015, we searched the MEDLINE, EMBASE, and CENTRAL databases, and the reference lists of retrieved articles, to identify relevant studies. Descriptions of antiviral drugs used to treat HBV-MN were included in our review. Two authors independently screened all relevant articles, extracted data, and assessed the risk of bias. Nine hundred and fifty-four papers have been considered after electronic and manual searching, only five relevant studies were identified. Complete remission (OR = 26.87, 95% CI: 8.06 to 89.52), total remission (OR = 10.31, 95% CI: 3.59 to 29.63) of proteinuria and HBeAg clearance (OR = 20.91, 95% CI: 6.90 to 63.39) increased significantly after antiviral therapy. No significant differences were seen between interferon and nucleoside analog treatments. Our study found that antiviral therapy was an effective treatment in HBV-MN patients; interferon and nucleoside analogs were equally effective at causing proteinuria remission and HBeAg clearance.