Yong Gu

Objective. The elder diabetic patients increases rapidly in China and often accompany with hyperuricemia. Recently evidences show that renal function has been impaired in part of diabetic patients with normoalbuminuria. Therefore, we investigated the relationship between serum uric acid (SUA) and renal function in Chinese elder diabetes with normoalbuminuria. Methods. The physical examination data from 1052 cases of diabetic residents with normoalbuminuria aged 70 years and over in the Jiangchuan community of Minhang District, Shanghai, from October 2011 to September 2014 was analyzed retrospectively. Each received height, body weight, waist circumference (WC), waist-to-hip ratio (WHR), blood pressure (BP), and collected samples of fasting blood and morning urine to detect blood routine, blood glucose, glycosylated hemoglobin (HbA1c), blood lipids, serum creatinine, urinary albumin, urine creatinine, and urine PH value. Correlation between SUA and renal function, an index of which is estimated using estimated glomerular filtration rate (eGFR), was analyzed. Results. The prevalence of hyperuricemia was 21.10%. Levels of WC and triglyceride (TG) increased and the levels of HbA1c, high density lipoprotein-cholesterol (HDL-C), eGFR, and urine PH decreased while the levels of SUA increased. Moreover, negative correlation of eGFR with age, WC, leukocyte, and SUA (Pearson r=0.415) was observed via Pearson correlation analysis. It indicates the strong association between SUA and eGFR. Furthermore, eGFR independently associated with SUA, age, leukocyte, hemoglobin (Hb), and fasting blood glucose (FBG) was confirmed by multiple linear stepwise regression analysis. Conclusion. SUA may play an important role in the decrease of eGFR in elderly Chinese diabetic patients with normoalbuminuria.

Background/aims: All chronic kidney disease (CKD) can eventually develop into renal fibrosis. We explored the renoprotective effects of a gastric peptide, ghrelin, and investigated whether endoplasmic reticulum stress (ERS) and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome mediate the protective effect of ghrelin in unilateral ureteral obstruction (UUO). Methods: Male C57BL/6J mice were divided into vehicle- or ghrelin-treated sham-operated groups and vehicle- or ghrelin treated UUO groups. The kidneys were harvested on postoperative day 14. Renal fibrosis was evaluated by periodic acid-Schiff, Masson trichrome, and immunohistochemical (IHC) staining. To assess renal fibrosis, a-smooth muscle actin and type I collagen were detected. NLRP3 inflammasome and ERS activation were also detected via western blotting. The effect of ghrelin on cultured renal cells was further confirmed in HK-2 cells. Results: Compared with the sham mice, UUO mice developed obvious renal fibrosis; pathological and IHC staining showed increased matrix accumulation and elevated ERS, NLRP3 inflammasome was activated both in vivo and in vitro. Ghrelin significantly attenuated collagen fibril accumulation and apoptosis by reducing NLRP3 inflammasome activation and ERS in obstructed kidneys. Conclusions: Ghrelin may attenuate UUO-induced renal fibrosis by inhibiting the NLRP3 inflammasome and ERS in vivo. Therefore, ghrelin might be an effective strategy for preventing CKD.

The mechanisms of proteinuria development in preeclampsia (PE) are still enigmatic. Renin–angiotensin system (RAS) components may play a role. Maternal serum and urinary concentrations of angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II), and angiotensinogen in women with PE (n = 14), gestational hypertension (n = 14), and normal pregnancy were quantified. The alteration in these concentrations was used to evaluate their relationships with podocyturia and proteinuria in PE. In addition, the podocytes cultured in vitro were interfered in serum of preeclamptic and normotensive pregnant women, with or without Ang-(1-7). The morphologic change in podocyte was observed using a microscope. The changes in podocyte-specific proteins (nephrin, CD2-associated protein [CD2AP]), the cytoskeletal protein F-actin, the tight junction protein (ZO-1), and Mas receptor (MasR) were examined by immunofluorescence. Western blot was used to examine the expression and variation of MasR. We found that the concentrations of RAS components were associated with prepartal urinary podocyte number, random urine albumin/creatinine ratio, blood pressure, and renal function. The expression of nephrin, F-actin, ZO-1, and MasR on podocytes interfered in serum of PE was significantly decreased compared to normal control and normal pregnant serum group in vitro, yet their expression was significantly increased after coculture by 10⁻⁶mol/L Ang-(1-7) and the preeclamptic serum. The expression of CD2AP had no significant difference. We concluded that decreased Ang-(1-7) and downregulated intrarenal RAS contributed to the direct podocyte injury with proteinuria in PE.

Electroacupuncture (EA) may stimulate neurogenesis in animal models of ischemic stroke; however, the associated mechanisms are not clear. The present study aimed to evaluate the neurogenesis efficacy of EA on ischemic stroke and the underlying associated mechanisms. A model of middle cerebral artery occlusion (MCAO) was employed as the rat model of brain ischemia and reperfusion. EA treatment at the GV20 (Baihui) and GV14 (Dazhui) acupoints was conducted for 30 min daily following MCAO. Immunofluorescence was performed to measure the number of bromodeoxyuridine (BrdU)/nestin‑ or BrdU/doublecortin (DCX)‑positive cells in the sham, MCAO and MCAO + EA groups. Results indicated that EA stimulation significantly decreased the neurological score and neuronal loss in rats in the MCAO group (both P<0.05). Furthermore, immunostaining assays indicated that BrdU/nestin‑ and BrdU/DCX‑positive cells in EA‑treated rats were significantly increased (P<0.05) when compared with the rats in the MCAO group, indicating EA may induce the proliferation and differentiation of endogenous neural stem cells (eNSCs) during cerebral ischemia‑reperfusion. In addition, EA treatment significantly enhanced the protein expression levels of plasticity‑related gene 5 (PRG5), a critical neurogenesis factor, and significantly decreased the protein expression levels of three neurogenesis inhibiting molecules, NogoA, lysophosphatidic acid and RhoA (all P<0.05). These results suggested that EA promotes the proliferation and differentiation of eNSCs, likely through modulating PRG5/RhoA signaling.

To investigate the role of glucagon-like peptide-1 analog (GLP-1) in high-fat diet-induced obesity-related glomerulopathy (ORG). Male C57BL/6 mice fed a high-fat diet for 12 wk were treated with GLP-1 (200 μg/kg) or 0.9% saline for 4 wk. Fasting blood glucose and insulin and the expression of podocin, nephrin, phosphoinositide 3-kinase (PI3K), glucose transporter type (Glut4), and microtubule-associated protein 1A/1B-light chain 3 (LC3) were assayed. Glomerular morphology and podocyte foot structure were evaluated by periodic acid-Schiff staining and electron microscopy. Podocytes were treated with 150 nM GLP-1 and incubated with 400 μM palmitic acid (PA) for 12 h. The effect on autophagy was assessed by podocyte-specific Glut4 siRNA. Insulin resistance and autophagy were assayed by immunofluorescence and Western blotting. The high-fat diet resulted in weight gain, ectopic glomerular lipid accumulation, increased insulin resistance, and fusion of podophyte foot processes. The decreased translocation of Glut4 to the plasma membrane and excess autophagy seen in mice fed a high-fat diet and in PA-treated cultured podocytes were attenuated by GLP-1. Podocyte-specific Glut4 siRNA promoted autophagy, and rapamycin-enhanced autophagy worsened the podocyte injury caused by PA. Excess autophagy in podocytes was induced by inhibition of Glut4 translocation to the plasma membrane and was involved in the pathology of ORG. GLP-1 restored insulin sensitivity and ameliorated renal injury by decreasing the level of autophagy.

Background: The clinical assessment of kidney function based on the estimated glomerular filtration rate (GFR) in older patients remains controversial. This study evaluated the concordance and feasibility of using various creatinine-based equations for estimating GFR in elderly Chinese patients with type 2 diabetes mellitus (T2DM). Methods: A cross-sectional analytical study was conducted in 21,723 older diabetic patients (≥60 years) based on electronic health records (EHR) for Minhang District, Shanghai, China. The concordance of chronic kidney disease (CKD) classification among different creatinine-based equations was assessed based on Kappa values, intraclass correlation coefficient (ICC) statistics, and the eGFR agreement between the equations was tested using Bland–Altman plots. The GFR was estimated using the Cockcroft–Gault (CG), Berlin Initiative Study 1 (BIS1), simplified Modification of Diet in Renal Disease (MDRD), MDRD modified for Chinese populations (mMDRD), chronic kidney disease epidemiology collaboration (CKD-EPI), CKD-EPI in Asians (CKD-EPI-Asia), and Ruijin equations. Results: Overall, the proportion of CKD stages 3–5 (eGFR 2) was calculated as 28.9%, 39.1%, 11.8%, 8.4%, 14.3%, 11.5%, and 12.7% by the eGFR_CG, eGFR_BIS1, eGFR_MDRD, eGFR_mMDRD, eGFR_CKD-EPI, eGFR_CKD-EPI-Asia, and eGFR_Ruijin equations, respectively. The concordance of albuminuria and decreased eGFR based on the different equations was poor by both the Kappa (Conclusion: Accurate GFR values are difficult to estimate using creatinine-based equations in older diabetic patients. Kidney function is complex, and the staff need to be aware of the individualized consideration of other risk factors or markers of reduced renal function in clinical practice.

Aims: The study aimed to investigate the renoprotective effect of glucagon-like peptide-1 (GLP-1) against renal tubular injury in C57BL/6 mice induced by a high-fat diet (HFD). Methods: Twenty C57BL/6 mice were fed HFD for 12 weeks. Ten of these mice were treated with GLP-1 at 200 µg/kg subcutaneously twice daily for 4 weeks (HFDG group), and the other ten mice received vehicle only (HFD group). Ten mice fed standard rodent chow served as controls (Con group). Body weight, kidney weight, food intake, and systolic blood pressure were measured. The expression of endoplasmic reticulum stress (ERS) markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis in the kidney were examined utilizing western blotting, immunohistochemistry and TUNEL, respectively. Angiotensin II and angiotensin II type 1 receptor (AT1R) were examined by ELISA. Human proximal tubule epithelial cells (HK2) were treated with GLP-1(150 nM) followed by treatment with palmitic acid (500 nM [PA]) for 24 h. HK2 cells treated with BSA were used as controls. The protein levels of ERS markers, apoptosis-associated protein, and AT1R were measured by western blotting. Results: Increase of body weight, food intake, and systolic blood pressure was less pronounced in GLP-1 treated HFDG mice compared to HFD mice. The levels of ERS markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis decreased following GLP-1 treatment in vivo and in vitro (pConclusion: The study indicated that saturated fatty acids induced ERS and apoptosis in the kidney and increased AT1R expression. GLP-1 treatment exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell ERS and apoptosis together with inhibition of AT1R expression in vivo and in vitro.

Aldosterone (Aldo) is critically involved in the development of renal injury via the production of reactive oxygen species and inflammation. Endoplasmic reticulum (ER) stress is also evoked in Aldo-induced renal injury. In the present study, we investigated the role of ER stress in inflammation-mediated renal injury in Aldo-infused mice. C57BL/6J mice were randomized to receive treatment for 4 weeks as follows: vehicle infusion, Aldo infusion, vehicle infusion plus tauroursodeoxycholic acid (TUDCA), and Aldo infusion plus TUDCA. The effect of TUDCA on the Aldo-infused inflammatory response and renal injury was investigated using periodic acid-Schiff staining, real-time PCR, Western blot, and ELISA. We demonstrate that Aldo leads to impaired renal function and inhibition of ER stress via TUDCA attenuates renal fibrosis. This was indicated by decreased collagen I, collagen IV, fibronectin, and TGF-β expression, as well as the downregulation of the expression of Nlrp3 inflammasome markers, Nlrp3, ASC, IL-1β, and IL-18. This paper presents an important role for ER stress on the renal inflammatory response to Aldo. Additionally, the inhibition of ER stress by TUDCA negatively regulates the levels of these inflammatory molecules in the context of Aldo.