Renal Function In Diabetic Mice Research Articles

T-Fiber, A Highland Barley Fiber-Rich Powder, Alleviates Hyperglycemia and Improves Kidney Pathology in Db/db Mice

The role of dietary fiber in highland barley in lowering blood lipids has been continuously studied in recent years. However, its effects on diabetes and diabetic nephropathy are rarely studied. Considering that highland barley bran is rich in dietary fiber, the effective use of dietary fiber in highland barley bran can not only alleviate the symptoms of diabetes but also improve the local economy. This article aimed to study the effects of highland barley fiber-rich powder (T-fiber) with a high-quality natural dietary fiber ratio (insoluble fiber/soluble fiber = 3 : 1) on the symptoms of hyperglycemia in a diabetic mouse model. Compared with the model group’s blood glucose level (30.80 mmol/L), glucose tolerance (28.57 mmol/L), and glycosylated serum protein (2.43 mmol/L), T-fiber presented significant reductions in blood glucose (23.69 mmol/L), better glucose tolerance (21.32 mmol/L), and glycosylated serum protein (1.78 mmol/L) in the diabetic mouse model. Meanwhile, T-fiber effectively alleviated hepatocellular lesions. In addition, T-fiber not only improved kidney function by reducing the 24-hour urine output (8.25 ml), urine protein levels (11.51 mg), and serum creatinine (13.80 μmol/L) but also alleviated renal pathology, including glomerular hypertrophy, mesangial expansion, and fibrosis. The above results proved the ability of T-fiber to reduce blood glucose and alleviate liver and renal function in diabetic mice. Altogether, T-fiber is a capable formula for utilizing highland barley bran dietary fiber, which alleviates diabetes symptoms and endows highland barley with promising value.

Breviscapine alleviates podocyte injury by inhibiting NF-κB/NLRP3-mediated pyroptosis in diabetic nephropathy.

Podocyte injury is a critical factor in the pathogenesis of diabeticnephropathy (DN). Emerging evidence has demonstrated that breviscapine (Bre) exerts a renoprotective effect on diabetic rats. However, the effects of Bre on regulating podocyte injury under high glucose (HG) conditions remain unclear. In this study, an experimental mouse model of DN was induced by intraperitoneal injections of streptozotocin (STZ) in vivo. The effects of Bre on podocyte injury were assessed using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTPnick-endlabelling (TUNEL) staining, quantitative real-time PCR (qRT‒PCR) and western blot analysis. We found that renal function was significantly decreased in diabetic mice, and this effect was blocked by Bre treatment. Bre effectively increased podocyte viability and inhibited HG-induced cell apoptosis. Furthermore, Bre ameliorated HG-induced podocyte injury, as evidenced by decreased α-smooth muscle actin (α-SMA) expression and increased podocin and synaptopodin expression. Mechanistically, Bre inhibited HG-induced nuclear factorkappaB (NF-κB) signalling activation and subsequently decreased NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in a decrease in pyroptosis. Pharmacological inhibition of NLRP3 decreased HG-induced podocyte injury, whereas the NLRP3 agonist abrogated the effects of Bre on inhibiting podocyte injury. In summary, these results demonstrate that Bre alleviates HG-induced podocyte injury and improves renal function in diabetic mice, at least in part by inhibiting NF-κB/NLRP3-mediated pyroptosis.

Jujuboside A ameliorates tubulointerstitial fibrosis in diabetic mice through down-regulating the YY1/TGF-β1 signaling pathway.

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus, which is characterized in renal tubulointerstitial fibrosis (TIF). The current study was designed to investigate the protective effect of Jujuboside A (Ju A) on TIF in type 2 diabetes (T2DM) mice, and explore its underlying anti-fibrosis mechanism. A mouse T2DM model was established using high fat diet (HFD) feeding combined with intraperitoneal injection of streptozotocin (STZ). Then, diabetic mice were treated with Ju A (10, 20 and 40 mg·kg-1·d-1, i.g.) for 12 weeks. Results showed that administration of Ju A not only down-regulated fasting blood glucose (FBG) levels, but also improved hyperlipidemia and renal function in diabetic mice. Moreover, the reduced ECM accumulation was observed in the renal cortex of Ju A treated diabetic mice, while the TIF progression was also attenuated by Ju A through blocking the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs). Further mechanism studies showed that Ju A treatment effectively down-regulated the protein expression and subsequent nuclear translocation of Yin Yang 1 (YY1) in the renal cortex of diabetic mice, and reduced the levels of transforming growth factor-β1 (TGF-β1) in the serum and renal cortex of Ju A treated mice. According to invitro studies, the up-regulated YY1/TGF-β1 signaling pathway was restored by Ju A in high glucose (HG) cultured HK-2 cells. Taken together, these findings demonstrated that Ju A can ameliorate the TIF of DN through down-regulating the YY1/TGF-β1 signaling pathway.

β-LAPachone is renoprotective in streptozotocin-induced diabetic mice via regulating the PI3K/Akt/mTOR signaling pathway.

Objective(s):β-LAPachone (B-LAP) is a natural product with established anti-inflammatory properties. In this study, we investigated the protective potential of B-LAP against diabetic nephropathy in streptozotocin (STZ) induced diabetic mice.Materials and Methods: Diabetes induction in mice was carried out by a single intraperitoneal injection of STZ. 2.5 mg/kg/day and 5 mg/kg/day doses of B-LAP were administered orally for twelve weeks and renal histoarchitecture, caspase-3, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), glutathione peroxidase (GPX), as well as urinary nephrin and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated. Additionally, kidney levels of PI3K, phosphorylated (p)-Akt, p-mTOR, p-CREB, and SIRT1 were assessed in the present investigation.Results: 5 mg/kg B-LAP significantly decreased urinary excretions of nephrin and NGAL. It also mitigated renal TNF-α and MDA levels and simultaneously improved GPX activities. 5 mg/kg B-LAP improved renal function in diabetic mice as indicated by elevated values of creatinine clearance. While B-LAP elevated renal levels of SIRT1, it alleviated PI3K, p-Akt, p-mTOR, and p-CREB levels in the kidneys of diabetic mice.Conclusion:Collectively, these findings suggest B-LAP as a potential renoprotective agent in STZ-induced diabetic mice probably via modulating the PI3K/Akt/mTOR pathway.

Isoliquiritigenin prevents hyperglycemia-induced renal injuries by inhibiting inflammation and oxidative stress via SIRT1-dependent mechanism

Diabetic nephropathy (DN) as a global health concern is closely related to inflammation and oxidation. Isoliquiritigenin (ISL), a natural flavonoid compound, has been demonstrated to inhibit inflammation in macrophages. Herein, we investigated the effect of ISL in protecting against the injury in STZ-induced type 1 DN and in high glucose-induced NRK-52E cells. In this study, it was revealed that the administration of ISL not only ameliorated renal fibrosis and apoptosis, but also induced the deterioration of renal function in diabetic mice. Mediated by MAPKs and Nrf-2 signaling pathways, respectively, upstream inflammatory response and oxidative stress were neutralized by ISL in vitro and in vivo. Moreover, as further revealed by the results of molecular docking, sirtuin 1 (SIRT1) binds to ISL directly, and the involvement of SIRT1 in ISL-mediated renoprotective effects was confirmed by studies using in vitro models of SIRT1 overexpression and knockdown. In summary, by reducing inflammation and oxidative stress, ISL has a significant pharmacological effect on the deterioration of DN. The benefits of ISL are associated with the direct binding to SIRT1, the inhibition of MAPK activation, and the induction of Nrf-2 signaling, suggesting the potential of ISL for DN treatment.

Angiotensin-converting enzyme 2 influences pancreatic and renal function in diabetic mice

AbstractType 1 diabetes is a T-cell mediated autoimmune disease characterized by pancreatic beta cells destruction. Angiotensin-converting enzyme 2 (ACE2), a component of renin–angiotensin system (RAS) has been identified in pancreas from type 2 diabetic mice and its overexpression prevents beta cell dysfunction. We studied the effect of ACE2 deletion on pancreatic and renal function in the nonobese diabetic mice, a model that mimics type 1 diabetes. ACE2-deficient NOD mice and the respective controls were generated. Pancreas function and immunohistochemistry studies were performed. Renal function and RAS gene expression were also analyzed. Renal proximal tubular cells were obtained from these animals to dissect the effect of ACE2 deficiency in these cells. In NOD mice, ACE2 deletion significantly worsened glucose homeostasis, decreased islet insulin content, increased beta cell oxidative stress, and RIPK1-positive islets as compared with control mice. Angiotensin-converting enzyme and angiotensin II type 1 receptor (AT1R) were also increased in ACE2-deficient mice. In kidneys of 30-day diabetic mice, ACE2 deletion decreased podocyte number within the glomeruli, and altered renal RAS gene expression in tubules. ACE2 deletion influenced the expression of fibrosis-related genes in isolated primary renal proximal tubular cells before diabetes onset in NOD mice. Our findings suggest that ACE2 deletion may have a deleterious impact on beta cell and renal function, by promoting oxidative stress and increasing necroptosis mediators. In addition, this effect is accompanied by RAS alterations in both pancreas and renal proximal tubular cells, indicating that ACE2 may exert a renopancreatic protective effect on type 1 diabetes, which is activated before diabetes starts.This study examined the contribution of ACE2 in diabetes onset and the role of ACE2 in the progression of diabetic nephropathy in NOD mouse. ACE2 loss leads to an impaired glucose and insulin homeostasis, RAS activation, increase in oxidative stress, and RIPK1 within the pancreas. In the kidney, ACE2 deletion induced podocyte loss, RAS modulation, and renal fibrosis activation in an early phase of diabetes.

Protective Effects of the Segmental Renal Artery Clamping Technique on Ischemia-Reperfusion Injury in db/db Diabetic Mice.

Renal ischemia-reperfusion (I/R) injury is inevitable in partial nephrectomy and other kidney surgeries, with a higher incidence in patients with renal insufficiency. This study aimed to investigate the protective effects of precise segmental renal artery clamping (SRAC) against renal I/R injury in db/db diabetic mice, compared with conventional renal artery clamping (RAC). Grape seed extract, a powerful free radical scavenger, was administered to diabetic mice for 4 weeks before operation in subgroups (30 mg/kg/d). The unilateral renal pedicle was ligatured, and I/R injury to the contralateral kidney was induced (ischemia for 30 min followed by reperfusion for 24 h). Blood glucose value, creatinine, blood urea nitrogen, and urine microalbumin/urine creatinine ratio increased gradually and showed no preoperative statistical differences among six subgroups. These parameters were significantly lower in the SRAC than in the RAC group 24 h postoperatively. Moreover, the nonischemic area in the SRAC group expressed less KIM-1 and TNF-α mRNA and also revealed minor histopathological damage induced by I/R. These findings suggest that SRAC effectively reduces early renal injury induced by I/R and accelerates the recovery of renal function in diabetic mice. Thus, SRAC may be an ideal technique in partial nephrectomy, especially for patients with diabetic nephropathy and other renal insufficiencies.

Hypoglycemic activity and potential mechanism of a polysaccharide from the loach in streptozotocin-induced diabetic mice.

The present study was designed to investigate the hypoglycemic activity and the potential mechanisms of Misgurnus anguillicaudatus polysaccharide (MAP) in streptozotocin-induced diabetic mice. MAP oral administration significantly decreased the blood levels of glucose, TC, TG, LDL-C, and increased the blood levels of HDL-C and insulin in diabetic mice, concurrent with increases in body weights and pancreatic insulin contents. Moreover, MAP reversed the increased mRNA expressions of PEPCK and the reduced glycogen contents in the liver of diabetic mice. Concurrently, MAP exhibited potent anti-inflammatory and anti-oxidative activities, as evidenced by the decreased blood levels of TNF-α, IL-6, monocyte chemoattractant protein-1, MDA, and also the elevated SOD and GPx activities in the serum of diabetic mice. Furthermore, MAP also significantly improved the blood markers of the impaired liver function and renal function in diabetic mice. Altogether, these results suggest that MAP may be a potential therapeutic option for type 1 diabetes.

Effects of Gum Arabic (Acacia senegal) on Renal Function in Diabetic Mice

Background/Aims: Gum arabic (GA) is a Ca²⁺-, Mg²⁺- and K⁺-rich dietary fiber used for the treatment of patients with chronic kidney disease in Middle Eastern countries. In healthy mice, GA treatment increases creatinine clearance, renal ADH excretion, as well as intestinal and renal excretion of Mg²⁺ and Ca²⁺. GA decreases plasma Pi concentration, urinary Pi and Na⁺ excretion. The present study explored the effects of GA on renal function in diabetic mice. Methods: Metabolic cage experiments were performed on Akita mice (akita^+/–), which spontaneously develop insulin deficiency and thus hyperglycemia. Plasma and urinary concentrations of Na⁺, K⁺ and Ca²⁺ were measured by flame photometry (AFM 5051, Eppendorf, Germany), creatinine by the Jaffé method, phosphate photometrically, urea by an enzymatic method, glucose utilizing a glucometer and an enzymatic kit, aldosterone using an RIA, urinary albumin fluorometrically, and blood pressure by the tail-cuff method. Results: GA (10% in drinking water) significantly increased urinary excretion of Ca²⁺ and significantly decreased plasma phosphate and urea concentrations, urinary flow rate, urinary Na⁺, phosphate and glucose excretion, blood pressure and proteinuria. Conclusions: GA treatment decreases blood pressure and proteinuria in diabetic mice and may thus prove beneficial in diabetic nephropathy.

The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy

Diabetic nephropathy is characterized by glomerular hypertrophy. We have recently shown that experimental diabetes mellitus is associated with an increase in glomerular expression of the cyclin kinase inhibitor p21WAF1/CIP1 (p21). Furthermore, in vitro glucose-induced mesangial cell hypertrophy is also associated with an up-regulated expression of p21. In this study, we tested the hypothesis that p21 mediates diabetic glomerular hypertrophy in vivo. Experimental diabetes mellitus was induced by streptozotocin in mice in which p21 was genetically deleted (p21 -/-) and in wild-type mice (p21 +/+). Kidney biopsies were obtained from diabetic and control (citrate injected) p21 +/+ and p21 -/- mice at day 60. The tissue was used for morphologic studies of glomerular size (measured by computer image-analysis system), glomerular cellularity (cell count), glomerular matrix expansion (silver stain), apoptosis (TUNEL), and expression of transforming growth factor-beta1 (TGF-beta1) by in situ hybridization. The glomerular tuft area increased 11.21% in diabetic p21 +/+ mice at day 60 compared with control (3329.98 +/- 244.05 micrometer(2) vs. 2994. 39 +/- 176.22 micrometer(2), P = 0.03), and the glomerular cell count did not change in diabetic p21 +/+ mice at day 60 compared with the control. These findings are consistent with glomerular hypertrophy. In contrast, the glomerular tuft area did not increase in diabetic p21 -/- mice at day 60 compared with the control (3544.15 +/- 826.49 vs. 3449.15 +/- 109.65, P = 0.82), nor was there an increase in glomerular cell count (41.41 +/- 13.18 vs. 46.95 +/- 3.00, P = 0.43). Diabetic p21 +/+ mice, but not p21 -/- mice, developed an increase in proteinuria at day 60 compared with the control. Tubular cell proliferation, measured by proliferating cell nuclear antigen immunostaining, was increased in both diabetic p21 +/+ (2.1-fold) and p21 -/- (7.61-fold) mice compared with controls. Glomerular cell apoptosis did not increase in diabetic mice. Although glomerular TGF-beta1 mRNA levels increased in both strains of diabetic mice at day 60, the glomerular matrix did not expand. Hyperglycemia was associated with glomerular hypertrophy in p21 +/+ mice. Despite the increase in TGF-beta1 mRNA, diabetic p21 -/- mice did not develop glomerular hypertrophy, providing evidence that the cyclin kinase inhibitor p21 may be required for diabetic glomerular hypertrophy induced by TGF-beta1. The loss of p21 increases tubular but not glomerular cell proliferation in diabetic nephropathy. The absence of glomerular hypertrophy appears protective of renal function in diabetic mice.