Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease.

INTRODUCTION: Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the protective effect and potential mechanism of vitamin D on podocyte injury of DKD. METHODS: Type 2 diabetic db/db mice received intraperitoneal injections of vitamin D analog paricalcitol 400 ng/kg per day for 16 weeks. Immortalized mouse podocytes were cultured in high glucose (HG) medium with active vitamin D3 calcitriol or autophagy inhibitor 3-methyladenine. Renal function and urine albumin creatinine ratio were assessed at week 24. HE, PAS staining, and electron microscopy were used to evaluate renal histopathology and morphological changes. Immunohistochemistry, immunofluorescence, and Western blot were used to evaluate protein expression of nephrin and podocin in kidney tissue and podocytes. The expression of autophagy-related proteins (LC3, Beclin-1, Vps34) and apoptosis-related proteins (cleaved caspase-3, Bax) was determined by Western blotting. Podocyte apoptosis was further evaluated by using flow cytometer. RESULTS: Albuminuria in a db/db mouse model was markedly attenuated after treatment with paricalcitol. This was accompanied by alleviation of mesangial matrix expansion and podocyte injury. Besides, the impaired autophagy in podocytes under diabetic conditions was also markedly enhanced after paricalcitol or calcitriol treatment, accompanied by restored decreased podocyte slit diaphragm proteins podocin and nephrin. Furthermore, the protective effect of calcitriol against HG-induced podocyte apoptosis could be abated by autophagy inhibitor 3-methyladenine. CONCLUSION: Vitamin D ameliorates podocyte injury of DKD by enhancing podocyte autophagy activity, which may become a potential candidate autophagy activator for the therapeutic interventions for DKD.

Effects of canagliflozin and metformin on insulin resistance and visceral adipose tissue in people with newly-diagnosed type 2 diabetes.

BACKGROUND: The current study was to evaluate the effects of canagliflozin and metformin on insulin resistance and visceral adipose tissue in people with newly-diagnosed type 2 diabetes. METHODS: This is an open-label, parallel and controlled study. Participants were divided into canagliflozin (100 mg/qd) or metformin (1000 mg/bid) groups. At baseline and after 12 weeks' therapy, insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], subcutaneous and visceral adipose tissue, fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), C-reactive protein (CRP) and nitric oxide (NO) were evaluated and compared. RESULTS: There was no significant between-group difference in baseline characteristics. After 12 weeks' therapy, in canagliflozin group (n = 67), compared to baseline, FBG, HbA1c and HOMA-IR were decreased, accompanying with reduction of visceral adipose tissue. Compared to metformin group (n = 73), FBG, HbA1c and HOMA-IR were lower in canagliflozin group, accompanying with less visceral adipose tissue and lower serum CRP level and higher NO level. After multivariable regression analysis, age, visceral adipose tissue and CRP remained associated with increased insulin resistance, while canagliflozin treatment and higher NO level were associated with reduced insulin resistance. Body mass index, waist/hip ratio, CRP and HOMA-IR remained associated with increased visceral adipose tissue, while canagliflozin treatment and higher NO level were associated with reduced visceral adipose tissue. There was no difference in adverse event between these two groups. CONCLUSION: Canagliflozin reduces visceral adipose tissue and improves blood glucose, insulin resistance and systemic inflammation in people with newly-diagnosed type 2 diabetes.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

Effects and Mechanisms of Dapagliflozin Treatment on Ambulatory Blood Pressure in Diabetic Patients with Hypertension.

BACKGROUND Studies have shown that dapagliflozin has antihypertensive effects. However, the effects and mechanisms of dapagliflozin on ambulatory blood pressure (ABP) have not been fully evaluated. In this study, we aimed to evaluate the effects of dapagliflozin treatment on ABP in patients with type 2 diabetes and hypertension. MATERIAL AND METHODS Patients were prospectively enrolled and divided into 2 groups: dapagliflozin treatment group (n=182) and no dapagliflozin treatment group (n=304). Clinical characteristics and measures of treatment, serum uric acid (SUA), 24-h urinary UA (UUA) excretion, and 24-h ABP were collected. The effects and mechanisms of dapagliflozin on 24-h ABP were evaluated. RESULTS After 3 months, the patients without dapagliflozin treatment had higher SUA, lower 24-h UUA excretion, and higher 24-h and daytime systolic blood pressure (SBP) (P<0.05) compared to patients with dapagliflozin treatment. After adjusting for covariates, results showed that dapagliflozin treatment was significantly associated with reduced 24-h SBP (ß=-0.29 and P=0.02) and reduced daytime SBP (ß=-0.33 and P=0.009). After additionally adjusting for SUA and 24-h UUA excretion, there were no significant relationships found between dapagliflozin treatment and 24-h (ß=-012, P=0.10) and daytime SBP (ß=-0.20, P=0.06). CONCLUSIONS In patients with diabetes and hypertension, dapagliflozin treatment was associated with reduced 24-h and daytime SBP, which could be related to the drug's effect of increasing 24-h UUA excretion.

Unusual conservative treatment of a complicated pacemaker pocket infection: a case report.

BACKGROUND: For patients with complicated generator pocket infection, expert consensuses universally advocate complete device and leads removal followed by delayed replacement on the contralateral side. We cured our patient by partial generator removal and reimplantation of sterilized pulse generator on the ipsilateral side. We also performed a literature review about incomplete removal therapy for the management of cardiac implantable electronic device infection. CASE PRESENTATION: An 86-year-old Chinese Han man was diagnosed as having third-degree atrioventricular block and received a permanent double-chamber pacemaker in his left prepectoral area 15 years ago. Nine years later, the entire system was removed because of confirmed infection, and a new device was reimplanted in the contralateral area. He developed skin necrosis around the pacemaker pocket after 1 year, and his generator was renewed without leads extraction at another medical center. He was subsequently admitted several times for surgical tissue debridement at another institution due to extended skin necrosis. At the time of the new admission, he had severe infection, heart failure, and hypoalbuminemia. He was diagnosed as having complicated pacemaker pocket infection. Our preferred treatment strategy was for complete removal of both the generator and transvenous pacing leads, and we intended to implant an epicardial pacemaker in our patient if necessary. However, he rejected the treatment strategy and firmly refused to replace his generator. We had to attempt a novel pacemaker-preserving strategy considering our patient's severe comorbidities. Finally, we cured him by partial generator removal and reimplantation of the sterilized pulse generator on the ipsilateral side. There was no sign of wound dehiscence or infection during a 6-month follow-up. CONCLUSIONS: We would posit that partial removal of infected generators combined with conservative treatment may be a proper treatment of complicated generator pocket infection, especially for those who are susceptible to cardiac complications. Reimplantation of a sterilized pulse generator on the ipsilateral side may be an option if patients reject a new device and contralateral vascular condition is not really suitable. Opting for such treatment should be at the consideration of the primary care physician based on the condition of the patient.