The Effects of Gluten-free Diet on Body Mass Indexes in Adults with Celiac Disease: A Systematic Review and Meta-analysis of Observational Studies.

GOALS AND BACKGROUND: Gluten-free diet (GFD) includes a higher intake of sugars and fats. Previous studies have investigated its effect on body mass index (BMI) in celiac disease (CD) patients but had contradictive conclusions. Thus, we conducted a systematic review and meta-analysis examining the effect of GFD on BMI in CD patients. STUDY: Systematically, we conducted literature research using Medline, Scopus, and Embase, and we identified 1565 potential studies/abstracts. Only studies of patients with CD under a GFD with recorded BMI before and after dietary intervention were included. Subgroup analyses based on study design and BMI categories were performed. We calculated the pooled odds ratios (ORs) and 95% confidence intervals (Cls) for the number of patients in each BMI group according to the World Health Organization (WHO) definitions after GFD using fixed and random effect meta-analysis. RESULTS: The analysis included 10 studies and 38 sub-studies/data sets, which encompassed 2450 patients from 5 countries. We found nonsignificant odds for changing the BMI group (pooled OR 0.972, 95% CI: 0.858-1.101, P=0.65) after GFD. However, looking specifically at BMI subgroups, we found higher odds for BMI category change after GFD in underweight patients (OR 0.588, 95% CI: 0.479-0.723, P <0.001), and overweight patients,25

Humoral Response to the Third Dose of BNT162b2 COVID-19 Vaccine among Hemodialysis Patients.

BACKGROUND: Hemodialysis patients are at high risk for severe COVID-19 disease. Despite a high early seropositivity rate, dialysis patients mount a dampened immune response following two doses of an mRNA vaccine. This study aimed to evaluate the serologic response to a booster dose of BNT162b2 vaccine, 6 months after the second dose, among hemodialysis patients. METHODS: This prospective study included 80 hemodialysis patients and 56 healthcare workers serving as controls. Serologic samples were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were the seropositivity rate and the log-transformed anti-SARS-COV-2 S1 (RBD) IgG as a continuous variable after the third dose. Secondary outcomes were the proportion of participants with "high response," defined as antibody levels >1,000 AU/mL, and "robust response," defined as antibody levels >4,160 AU/mL, according to prespecified cutoff values associated with neutralizing antibodies. Univariate and multivariate analyses were conducted to identify predictors of antibody response. RESULTS: Among 80 hemodialysis patients, seropositivity rates improved from 78% (62/80) before the third dose, up to 96% (77/80) after the booster dose. The S1-RBD log-transformed antibody level increased significantly following the third dose from 2.15 ± 0.75 to 3.99 ± 0.83 compared with 2.65 ± 0.4 to 4.31 ± 0.42 in the control group. Among the hemodialysis patients, 88% (70/80) became "high responders" (>1,000 AU/mL), and of these, 79% (63/80) mounted a "robust response" (>4,160 AU/mL). Baseline antibody level, dialysis therapy, and hypoalbuminemia were independent predictors of impaired antibody response. CONCLUSIONS: A third dose of BNT162b2 COVID-19 vaccine, 6 months after the standard two-dose vaccination regimen, substantially improved humoral response in hemodialysis patients.

BNT162b2 Booster Vaccination Induced Immunity against SARS-CoV-2 Variants among Hemodialysis Patients.

Background: The emergence of new SARS-CoV-2 variants, which evade immunity, has raised the urgent need for multiple vaccine booster doses for vulnerable populations. In this study, we aimed to estimate the BNT162b2 booster effectiveness against the spread of coronavirus variants in a hemodialysis population. Methods: We compared humoral and cell-mediated immunity in 100 dialysis patients and 66 age-matched volunteers, before and 2-3 weeks following the first booster vaccine dose. Participants were assessed for anti-spike (RBD) antibody titer, neutralizing antibodies against B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants, spike-specific T-cell responses by FACS and infection outbreak after the first and second booster. Results: Anti-spike antibody titer was significantly increased following the booster, with reduced humoral and cellular response in the dialysis patients. Neutralizing antibody levels increased significantly after the booster dose, with an inferior effect (≤2 fold) against Omicron compared with the Delta variant. Furthermore, CD4+ and CD8+ T-cell activation by Delta spike protein was preserved in 70% of PBMCs from the dialysis patients. A second booster dose tended to reduce breakthrough infections in the dialysis patients. Conclusions: Until the release of an updated vaccine, BNT162b2 booster doses will improve the humoral and cell-mediated immunity against variants. These findings support the importance of repetitive booster doses for hemodialysis patients.

Immune Response to Third Dose BNT162b2 COVID-19 Vaccine Among Kidney Transplant Recipients-A Prospective Study.

Immune response to two SARS-CoV-2 mRNA vaccine doses among kidney transplant recipients (KTRs) is limited. We aimed to evaluate humoral and cellular response to a third BNT162b2 dose. In this prospective study, 190 KTRs were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were anti-spike antibody level >4160 AU/ml (neutralization-associated cutoff) and any seropositivity. Univariate and multivariate analyses were conducted to identify variables associated with antibody response. T-cell response was evaluated in a subset of participants. Results were compared to a control group of 56 healthcare workers. Among KTRs, we found a seropositivity rate of 70% (133/190) after the third dose (37%, 70/190, after the second vaccine dose); and 27% (52/190) achieved levels above 4160 AU/ml after the third dose, compared to 93% of controls. Variables associated with antibody response included higher antibody levels after the second dose (odds ratio [OR] 30.8 per log AU/ml, 95% confidence interval [CI]11-86.4, p < 0.001); and discontinuation of antimetabolite prior to vaccination (OR 9.1,95% CI 1.8-46.5, p = 0.008). T-cell response was demonstrated in 13% (7/53). In conclusion, third dose BNT162b2 improved immune response among KTRs, however 30% still remained seronegative. Pre-vaccination temporary immunosuppression reduction improved antibody response.

Longevity of Humoral Response Six Months Following BNT162b2 Vaccine in Dialysis Patients.

Background: End-stage kidney disease substantially increases the risk of severe COVID-19. However, despite early robust immunogenicity of the mRNA-SARS-CoV-2 vaccination in patients with hemodialysis, the longevity of humoral response in this high-risk population is still unknown. Methods: A prospective cohort study aimed to evaluate the longevity of serologic response in patients with hemodialysis, compared with a control group, 6 months following the second dose of the BNT162b2 vaccine. We assessed antibody response by quantitative measurement of IgG antibodies against the receptor-binding domain of the Spike protein (anti-S1-RBD IgG). Study outcomes were defined as a seropositivity rate and log-transformed anti-S1-RBD IgG levels at 6 months, and the change in antibody levels between 3 and 6 months. Findings: The cohort included 104 patients with hemodialysis and 84 controls. At a median time of 184 days (IQR, 183-188) following the second dose of the vaccine, 83/104 (79.8%) patients with hemodialysis maintained seropositivity for the anti-S1-RBD IgG level compared to 83/84 (98.8%) in the control group (p < 0.001). The log-transformed antibody level was significantly lower in the hemodialysis group (2.23 ± 0.39 log AU/ml vs. 2.69 ± 0.65 log AU/ml, respectively, p < 0.001). Older age and hypoalbuminemia were the only variables that were found to be associated with reduced log-transformed antibody levels in univariate and multivariate analysis. There was no interaction between dialysis status and an antibody-level decline rate (p = 0.972). Conclusion: Among patients with hemodialysis, a seropositivity rate and anti-S1-RBD antibody titers were substantially reduced compared with a control group, at 6 months following the second dose of the BNT162b2 vaccine. These findings support the prioritization of patients with hemodialysis for a third "booster" dose.

Obesity-Related Glomerulopathy: Clinical Management.

Obesity-related glomerulopathy (ORG) and other obesity-associated kidney diseases pose a major challenge to the treating nephrologist. We review the benefits of weight loss and optimal management of ORG and kidney disease in the setting of obesity. Therapeutic strategies in ORG were limited mainly in the past to weight loss through lifestyle interventions and bariatric surgery, antihypertensive treatment, and renin-angiotensin-aldosterone system blockade. Current approaches to obtain the desired weight loss include novel pharmacologic therapies that have been approved for the treatment of diabetes while offering kidney protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1-receptor agonists. This review focuses on the nephroprotective role of the renin-angiotensin-aldosterone system blockade and of these new pharmacologic agents, and on the renal effects of bariatric surgery in chronic kidney disease.

Occlusive Mesenteric Ischemia in Chronic Dialysis Patients.

BACKGROUND: Among dialysis patients, occlusive mesenteric vascular disease has rarely been reported. OBJECTIVES: To report on the experience of one center with regard to diagnosing and treating this complication. METHODS: The retrospective case-series involved six patients (3 females, 3 males; age 52-88 years; 5/6 were smokers) on chronic hemodialysis at a single center. All patients with symptoms suggestive of occlusive mesenteric disease and a subsequent angiographic intervention were included. Demographic, clinical, and laboratory data were collected from patient charts for the period before and after angioplasty and stenting of the mesenteric vessels. A Wilcoxon signed-rank test was used to compare the relevant data before and after the intervention. RESULTS: All participants had variable co-morbidities and postprandial abdominal pain, food aversion, and weight loss. CT angiography was limited due to heavy vascular calcifications. All underwent angioplasty with stenting of the superior mesenteric artery (4 patients) or the celiac artery (2 patients). All procedures were successful in resolving abdominal pain, malnutrition, and inflammation. Weight loss before was 15 ± 2 kg and weight gain after was 6 ± 2 kg. C-reactive protein decreased from 13.4 ± 5.2 mg/dl to 2.2 ± 0.4 mg/dl (P < 0.05). Serum albumin increased from 3.0 ± 0.2 g/dl to 3.9 ± 0.1 g/dl (P < 0.05). Two patients underwent a repeat procedure (4 years, 5 months, respectively). Follow-up ranged from 0.5-7 years. CONCLUSIONS: Occlusive mesenteric ischemia occurs among dialysis patients. The diagnosis requires a high degree of suspicion, and it is manageable by angiography and stenting of the most involved mesenteric artery.

The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation.

Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell-cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.

Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, obesity, and activation of the renin angiotensin system.

BACKGROUND: Diabetic and obese patients are at higher risk of severe disease and cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin-angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice. METHODS: Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in ACE2 mRNA and protein expression in heart tissue and serum. ACE2 expression was compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A and SGLT2i) were also tested. RESULTS: ACE2 gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with glycosylated hemoglobin (HbA1c), body mass index (BMI), and activation of the renin angiotensin system (RAS), and negatively correlated with ejection fraction. ACE2 was not differentially expressed in patients who were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prior to the operation. We found no correlation between plasma free ACE2 and cardiac tissue ACE2 expression. Transmembrane serine protease 2 (TMPRSS2), metalloprotease ADAM10 and ADAM17 that facilitate viral-ACE2 complex entry and degradation were increased in diabetic hearts. ACE2 expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment. CONCLUSION: Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on ACE2 expression in the heart further support their safety.

Novel extra cellular-like matrices to improve human ovarian grafting.

PURPOSE: To investigate if human ovarian grafting with pure virgin human recombinant collagen type-1 from bioengineered plant lines (CollPlant™) or small intestine submucosa (SIS) yields better implantation results for human ovarian tissue and which method benefits more when combined with the host melatonin treatment and graft incubation with biological glue + vitamin E + vascular endothelial growth factor-A. METHODS: Human ovarian tissue wrapped in CollPlant or SIS was transplanted into immunodeficient mice with/without host/graft treatment. The tissue was assessed by follicle counts (including atretic), for apoptosis evaluation by terminal deoxynucleotidyl transferase assay and for immunohistochemical evaluation of neovascularization by platelet endothelial cell adhesion molecule (PECAM) expression, and for identification of proliferating granulosa cells by Ki67 expression. RESULTS: Human ovarian tissue transplanted with CollPlant or SIS fused with the surrounding tissue and promoted neovascularization. In general, implantation with CollPlant even without additives promoted better results than with SIS: significantly higher number of recovered follicles, significantly fewer atretic follicles, and significantly more granulosa cell proliferation. Moreover, results with CollPlant alone seemed to be at least as good as those after host and graft treatments. CONCLUSIONS: CollPlant is a biomaterial without any potential risks, and grafting ovarian tissue with CollPlant is easy and the procedure may be easily modified, with limited or no foreseeable risks, for auto-transplantation in cancer survivors. Further studies are needed using other novel methods capable of enhancing neovascularization and reducing apoptosis and follicle atresia.

Dual inhibition of cannabinoid CB1 receptor and inducible NOS attenuates obesity-induced chronic kidney disease.

BACKGROUND AND PURPOSE: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB1 receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD. EXPERIMENTAL APPROACH: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB1 receptor/iNOS antagonist, MRI-1867 (3 mg·kg-1 ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB1 receptor antagonist (JD5037; 3 mg·kg-1 ), iNOS antagonist (1400W; 10 mg·kg-1 ), and pair feeding. Mice with high-fat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls. KEY RESULTS: Enhanced expression of CB1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling. CONCLUSIONS AND IMPLICATIONS: Collectively, our results highlight the therapeutic relevance of blocking CB1 receptors and iNOS in ameliorating obesity-induced CKD.

Consequences of Glomerular Hyperfiltration: The Role of Physical Forces in the Pathogenesis of Chronic Kidney Disease in Diabetes and Obesity.

BACKGROUND: Glomerular hyperfiltration (GH) is a hallmark of renal dysfunction in diabetes and obesity. Recent clinical trials demonstrated that SGLT2 inhibitors are renoprotective, possibly by abating hyperfiltration. The present review considers the current evidence for a cause-to-effect relationship between hyperfiltration-related physical forces and the development of chronic kidney disease (CKD). SUMMARY: Glomerular hyperfiltration is associated with glomerular and tubular hypertrophy. Hyperfiltration is mainly due to an increase in glomerular capillary pressure, which increases tensile stress applied to the capillary wall structures. In addition, the increased ultrafiltrate flow into Bowman's space heightens shear stress on the podocyte foot processes and body surface. These mechanical stresses lead to an increase in glomerular basement membrane (GBM) length and to podocyte hypertrophy. The ability of the podocyte to grow being limited, a mismatch develops between the GBM area and the GBM area covered by foot processes, leading to podocyte injury, detachment of viable podocytes, adherence of capillaries to parietal epithelium, synechia formation and segmental sclerosis. Mechanical stress is also applied to post-filtration structures, resulting in dilation of glomerular and tubular urinary spaces, increased proximal tubular sodium reabsorption by hypertrophied epithelial cells and activation of mediators leading to tubulointerstitial inflammation, hypoxia and fibrosis Key Messages: GH-related mechanical stress leads to both adaptive and maladaptive glomerular and tubular changes. These flow-related effects play a central role in the pathogenesis of glomerular disease. Attenuation of hyperfiltration is thus an important therapeutic target in diabetes and obesity-induced CKD.

Bile acid receptors and the kidney.

PURPOSE OF REVIEW: Bile acids act as activating signals of endogenous renal receptors: the nuclear receptor farnesoid X receptor (FXR) and the membrane-bound G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). In recent years, bile acids have emerged as important for renal pathophysiology by activating FXR and TGR5 and transcription factors relevant for lipid, cholesterol and carbohydrate metabolism, as well as genes involved in inflammation and renal fibrosis. RECENT FINDINGS: Activation of bile acid receptors has a promising therapeutic potential in prevention of diabetic nephropathy and obesity-induced renal damage, as well as in nephrosclerosis. During the past decade, progress has been made in understanding the biology and mechanisms of bile acid receptors in the kidney and in the development of specific bile acid receptor agonists. SUMMARY: In this review, we discuss current knowledge on the roles of FXR and TGR5 in the physiology of the kidney and the latest advances made in development and characterization of bile acid analogues that activate bile acid receptors for treatment of renal disease.

FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.

Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also examined the individual effects of the selective FXR agonist obeticholic acid (OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. INT-767 exerted coordinated effects on multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α, sirtuin 3, estrogen-related receptor-α, and Nrf-1; inhibition of endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767 prevented mitochondrial dysfunction and oxidative stress determined by fluorescence lifetime imaging of NADH and kidney fibrosis determined by second harmonic imaging microscopy. These results identify the renal signaling pathways regulated by FXR and TGR5, which may be promising targets for the treatment of nephropathy in diabetes and obesity.

Attempts to improve human ovarian transplantation outcomes of needle-immersed vitrification and slow-freezing by host and graft treatments.

PURPOSE: To investigate if needle-immersed vitrification or slow-freezing yields better implantation results for human ovarian tissue and which method benefits more when combined with the "improvement protocol" of host melatonin treatment and graft incubation with biological glue + vitamin E + vascular endothelial growth factor-A. METHODS: Human ovarian tissue was preserved by needle-immersed vitrification or slow-freezing and transplanted into immunodeficient mice, either untreated (groups A and C, respectively) or treated with the improvement protocol (groups B and D, respectively). Grafted and ungrafted slices were evaluated by follicle counts, apoptosis assay and immunohistochemistry for Ki67 and platelet endothelial cell adhesion molecule (PECAM). RESULTS: Follicle number in the recovered grafts was limited. The number of atretic follicles was significantly higher after vitrification with/without the improvement protocol and slow-freezing than that after slow-freezing + the improvement protocol. Stroma cell apoptosis was the lowest in the group D. PECAM staining showed a peripheral and diffuse pattern in the group D (mostly normal follicular morphology) and a diffuse pattern in all other groups (few follicles, mostly atretic), with significantly higher diffuse levels in the vitrification groups. Ki67 staining was identified in all normal follicles. Follicles did not survive transplantation in the vitrification groups. CONCLUSIONS: Ovarian sample preparation with slow-freezing + the improvement protocol appears to yield better implantation outcomes than needle-immersed vitrification with/without the improvement protocol. The real quality of frozen tissue can be assessed only after grafting and not after thawing/warming.

SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 PROTEIN INHIBITION DECREASES RENAL LIPID ACCUMULATION, INFLAMMATION, AND THE DEVELOPMENT OF NEPHROPATHY IN DIABETIC MICE.

There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. The second aim of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in the progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin, and urinary thiobarbituric acid-reacting substances. SGLT2 inhibition prevented renal lipid accumulation via inhibition of carbohydrate-responsive element-binding protein-ß, pyruvate kinase L, SCD-1, and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation and expression of p65, TLR4, MCP-1, and osteopontin. These effects were associated with reduced mesangial expansion, accumulation of the extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice.

Angiotensin converting-enzyme inhibition restores glomerular glycosaminoglycans in rat puromycin nephrosis.

BACKGROUND: Aberrant glomerular polyanionic charge of glycosaminoglycans (GAGs) and sialic acid expression has been observed in proteinuric human and experimental glomerular diseases. Angiotensin-converting enzyme inhibitors (ACEI) lower proteinuria and amend renal function deterioration via hemodynamic mechanisms. We tested the hypothesis that ACEI modulate proteinuria additionally by modifying glomerular GAGs. METHODS: In this study, we explored the effects of the ACEI enalapril on proteinuria and GAG synthesis in puromycin aminonucleoside (PAN)-treated rats. We employed cationic colloidal gold (CCG) localization in glomerular basement membranes (GBM) to identify GAGs by electron microscopy and determined sialic acid residues by immunohistochemical staining with lectins. To clarify ACEI effects on GAG production in vitro, we studied de novo GAG synthesis into newly synthesized proteoglycans in podocytes and mesangial cells using 35S incorporation. Cells were incubated with or without PAN, and with increasing doses of the ACEI enalaprilat. RESULTS: PAN rats developed severe proteinuria that was significantly improved by enalapril treatment. In non-treated PAN rats GBM GAGs were reduced, whereas in the enalapril-treated group GBM GAGs were significantly increased to control levels. Enalapril did not affect glomerular sialic acid. Furthermore, in cultured podocytes and mesangial cells PAN decreased de novo GAG synthesis, an effect which was significantly ameliorated by enalaprilat treatment. CONCLUSION: Treatment with ACEI improves permselectivity properties of the glomerular capillary wall by maintaining its GAG content. This finding provides an additional new mechanism, whereby ACEI exert anti-proteinuric effects.

Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.

The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.