Streptozotocin-induced Diabetic Nephropathy Research Articles

Deletion of IRE1α in podocytes exacerbates diabetic nephropathy in mice

Protein misfolding in the endoplasmic reticulum (ER) of podocytes contributes to the pathogenesis of glomerular diseases. Protein misfolding activates the unfolded protein response (UPR), a compensatory signaling network. We address the role of the UPR and the UPR transducer, inositol-requiring enzyme 1α (IRE1α), in streptozotocin-induced diabetic nephropathy in mice. Diabetes caused progressive albuminuria in control mice that was exacerbated in podocyte-specific IRE1α knockout (KO) mice. Compared to diabetic controls, diabetic IRE1α KO mice showed reductions in podocyte number and synaptopodin. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; the major changes included widening of podocyte foot processes and glomerular basement membrane. Activation of the UPR and autophagy was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD-Glom database demonstrated induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy. Thus, mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy and attenuation of the glomerular UPR and autophagy, implying a protective effect of IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways.

Methanolic extract of Merremia emarginata (Burm. f.) Hallier f. attenuates renal damage in streptozotocin-induced diabetic nephropathy in rats

IntroductionMerremia emarginata (syn: Ipomoea reniformis) is used by the traditional healers of the Tirunelveli district of Tamil Nadu and Nelliampathy hills of Kerala for the treatment of diabetes. It contains important phytoconstituents like scopoletin, quercetin, and kaempferol and is reported to have pharmacological activities like antidiabetic antioxidant, antihyperlipidemic, ACE inhibitory, and hypotensive. Diabetic kidney disease is a common microvascular complication seen in patients with long-term diabetes. This study aimed to investigate the efficacy of Merremia emarginata in attenuating diabetic kidney disease. Materials and methodsDiabetes was induced by a single i.p. injection of 55 mg/kg streptozotocin (STZ). The animals were divided into seven groups with six rats in the control group and seven each in the STZ, STZ + Standard drug Ramipril (STD), STZ + Low dose (LD) methanolic extract of Merremia emarginata (MEME), STZ + High dose (HD) MEME, STZ + STD + LD, and STZ + STD + HD groups. The renal function was assessed by estimating various parameters viz, blood glucose, serum and urine creatinine, urine albumin, blood urea nitrogen (BUN), glycosylated haemoglobin (HbA1c) levels, oxidative stress, and kidney hypertrophy. ResultsTreatment with Ramipril and HD MEME showed a decrease in blood glucose levels, urine albumin, a decrease in serum creatinine, an increase in urine creatinine, a decrease in BUN, HbA1c, kidney hypertrophy, and oxidative stress. The combination treatment of Ramipril and HD MEME showed a synergistic effect. ConclusionThe study revealed that MEME attenuates diabetic nephropathy and has the potential to be used in diabetic nephropathy either alone or as an adjuvant.

Scutellarin ameliorates diabetic nephropathy via TGF-β1 signaling pathway

Breviscapine, a natural flavonoid mixture derived from the traditional Chinese herb Erigeron breviscapus (Vant.) Hand-Mazz, has demonstrated a promising potential in improving diabetic nephropathy (DN). However, the specific active constituent(s) responsible for its therapeutic effects and the underlying pharmacological mechanisms remain unclear. In this study, we aimed to investigate the impact of scutellarin, a constituent of breviscapine, on streptozotocin-induced diabetic nephropathy and elucidate its pharmacological mechanism(s). Our findings demonstrate that scutellarin effectively ameliorates various features of DN in vivo, including proteinuria, glomerular expansion, mesangial matrix accumulation, renal fibrosis, and podocyte injury. Mechanistically, scutellarin appears to exert its beneficial effects through modulation of the transforming growth factor-β1 (TGF-β1) signaling pathway, as well as its interaction with the extracellular signal-regulated kinase (Erk) and Wnt/β-catenin pathways.Graphical

Multiomic study of the protective mechanism of Persicaria capitata (Buch.-Ham. ex D.Don) H.Gross against streptozotocin-induced diabetic nephropathy in Guizhou miniature pigs

BackgroundPersicaria capitata (Buch.-Ham. ex D.Don) H.Gross (P. capitata, PCB), a traditional drug of the Miao people in China, is potential traditional drug used for the treatment of diabetic nephropathy (DN). PurposeThe purpose of this study is to investigate the function of P. capitata and clarify its protective mechanism against DN. MethodsWe induced DN in the Guizhou miniature pig with injections of streptozotocin, and P. capitata was added to the pigs’ diet to treat DN. In week 16, all the animals were slaughtered, samples were collected, and the relative DN indices were measured. 16S rRNA sequencing, metagenomics, metabolomics, RNA sequencing, and proteomics were used to explore the protective mechanism of P. capitata against DN. ResultsDietary supplementation with P. capitata significantly reduced the extent of the disease, not only in term of the relative disease indices but also in hematoxylin-eosin-stained tissues. A multiomic analysis showed that two microbes (Clostridium baratii and Escherichia coli), five metabolites (oleic acid, linoleic acid, 4-phenylbutyric acid, 18-β-glycyrrhetinic acid, and ergosterol peroxide), four proteins (ENTPD5, EPHX1, ARVCF and TREH), four important mRNAs (encoding ENTPD5, EPHX1, ARVCF, and TREH), six lncRNAs (TCONS_00024194, TCONS_00085825, TCONS_00006937, TCONS_00070981, TCONS_00074099, and TCONS_00097913), and two circRNAs (novel_circ_0001514 and novel_circ_0017507) are all involved in the protective mechanism of P. capitata against DN. ConclusionsOur results provide multidimensional theoretical support for the study and application of P. capitata.

Nephroprotective properties of Achillea millefolium green-formulated Au NPs in streptozotocin-induced diabetic nephropathy in mice: Introducing a novel therapeutic drug for the treatment of nephropathy

We have reported biosynthesis of Au NPs by using Achillea millefolium aqueous extract under mild procedure. Various techniques like UV–Vis, TEM, FE-SEM, EDS-elemental mapping and ICP-OES were used to characterize present nanoparticles. In the in vivo condition, streptozotocin (STZ) with dose of 60 mg/kg was used intraperitoneally for inducing diabetes in 100 mature male mice. The negative control mice were treated with normal saline and other mice were treated with glibenclamide (0.5 mg/kg) and Au nanoparticles (10 and 40 μg/kg) by gavage for 20 days. Additionally, 20 diabetic mice were considered as positive control and received the normal saline. Gold nanoparticles reduced the raised concentrations of urea and blood glucose in biochemical assays and volumes and lengths of vessels, loop of Henle, collecting ducts, and distal and proximal tubules in stereological assays in comparison with the untreated group. According to the obtained findings, gold nanoparticles can ameliorate the raised levels of biochemical parameters and prevent kidney structure damage in STZ-induced diabetic mice.

Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy.

Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.

Agmatine ameliorates diabetes type 2-induced nephropathy in rats

Objective: To assess the nephroprotective potential of agmatine in a rat model of streptozotocin-induced diabetic nephropathy. Methods: A single dose of streptozotocin (40 mg/kg) coupled with a fructose diet induced diabetes in Wistar rats. Agmatine (40 and 80 mg/kg) was administered to rats for 12 weeks. The body weight and fasting blood glucose were measured weekly. Insulin level, urine output, total protein, albumin, blood urea nitrogen, creatinine, and cystatin-C were also determined at the end of the experiment. Furthermore, superoxide dismutase, glutathione, interleukin-1β, interleukin-6, and tumor necrosis factor-alpha were evaluated in kidney tissue. Histopathological study was also performed using hematoxylin and eosin staining. Results: Agmatine at both doses significantly increased final body weight, and lowered fasting blood glucose, urine output, insulin, total protein, albumin, blood urea nitrogen, creatinine, and cystatin-C levels compared with the diabetic group (P < 0.05). Inflammatory markers and antioxidant effect were significantly improved in agmatine-treated rats. Moreover, the histopathological changes in renal structure were ameliorated by agmatine treatment. Conclusions: Agmatine alleviates diabetic nephropathy by improving renal functions and reducing inflammation and oxidative stress. The molecular mechanisms of its nephroprotective actions need to be investigated in future study.

Evaluation of chicory leaf extract on chronic kidney disease model in streptozotocin-induced diabetic nephropathy

Evaluation of chicory leaf extract on chronic kidney disease model in streptozotocin-induced diabetic nephropathy

Effect of Prunetin on Streptozotocin-Induced Diabetic Nephropathy in Rats - a Biochemical and Molecular Approach.

In the modern era, chronic kidney failure due to diabetes has spread across the globe. Prunetin (PRU), a component of herbal medicines, has a broad variety of pharmacological activities; these may help to slow the onset of diabetic kidney disease. The anti-nephropathic effects of PRU have not yet been reported. The present study explored the potential nephroprotective actions of PRU in diabetic rats. For 28 days, nephropathic rats were given oral doses of PRU (20, 40, and 80 mg/kg). Body weight, blood urea, creatinine, total protein, lipid profile, liver marker enzymes, carbohydrate metabolic enzymes, C-reactive protein, antioxidants, lipid peroxidative indicators, and the expression of insulin receptor substrate 1 (IRS-1) and glucose transporter 2 (GLUT-2) mRNA genes were all examined. Histological examinations of the kidneys, liver, and pancreas were also performed. The oral treatment of PRU drastically lowered the blood glucose, HbA1c, blood urea, creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, lipid profile, and hexokinase. Meanwhile, the levels of fructose 1,6-bisphosphatase, glucose-6-phosphatase, and phosphoenol pyruvate carboxykinase were all elevated, but glucose-6-phosphate dehydrogenase dropped significantly. Inflammatory marker antioxidants and lipid peroxidative markers were also less persistent due to this administration. PRU upregulated the IRS-1 and GLUT-2 gene expression in the nephropathic group. The possible renoprotective properties of PRU were validated by histopathology of the liver, kidney, and pancreatic tissues. It is therefore proposed that PRU (80 mg/kg) has considerable renoprotective benefits in diabetic nephropathy in rats.

Evaluation of the nephroprotective properties of silver nanoparticles formulated by Pistacia atlantica aqueous extract under ultrasonic condition in streptozotocin-induced diabetic nephropathy in mice

Green formulated silver nanoparticles offer a great promise in biomedicine. Administration of streptozotocin causes severe hepatotoxicity and nephrotoxicity by increasing the blood glucose. The development of nephroprotective drugs through eco-friendly production routes is a major challenge for current pharmacology and nanotechnology. The creation of cutting-edge technology for the synthesis of effective nephroprotective agents is crucial on a global scale. So in the current study, we report herein the bio-inspired proficient preparation of silver NPs over Pistacia atlantica (P.a.) aqueous extract as natural reducing/capping and stabilizing agent (P.a./Ag NPs) under ultrasonic irradiation. The final hybrid nanocomposite was thereafter characterized by a range advanced analytical methods like, FE-SEM, ICP-OES, EDX, TEM, and elemental mapping. Diabetes was induced by administration of 60 mg/kg of streptozotocin (STZ) intraperitoneally in 100 mature male mice and they were randomly divided into 5 groups. The negative control group received normal saline and treatment groups received glibenclamide with dose 0.5 mg/kg and 10 and 40 μg/kg of P.a./Ag nanocomposite through gavage for 50 days. On the last day, serum levels of samples blood glucose, urea and creatinine were measured. After tissue processing, 5 μm sections of the kidneys were prepared and they were stained by periodic acid Schiff (PAS) and used for stereological analysis. The kidney weight, kidney volume (Volume of cortex, medulla, glomerulus, proximal and distal tubules, collecting ducts, loop of Henle, interstitial tissues, and vessels) and kidney structures length (length of proximal and distal tubules, collecting ducts, loop of Henle, and vessels) decreased significantly (p ≤ 0.05) after treatment with high dose of P.a./Ag NPs nanocomposite (p > 0.05). The increased levels of blood glucose and urea were decreased (p ≤ 0.05) significantly in P.a./Ag nanocomposite-treated groups as compared to the untreated diabetic. This study suggested using from P.a./Ag nanocomposite as an antidiabetic and nephroprotective drug in the developing countries.

Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis

Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H2O2), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.

Enhanced Levels of Glycosphingolipid GM3 Delay the Progression of Diabetic Nephropathy.

We recently found that albuminuria levels in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) inversely correlate with glycosphingolipid GM3 expression levels in glomerular podocytes. Moreover, we showed enhanced expression of GM3 via activation of the GM3 synthase gene upon administration of valproic acid (VPA) is effective in suppressing albuminuria and podocyte injury in mice with anti-nephrin antibody-induced podocytopathy. However, the therapeutic effect of GM3 on diabetic nephropathy, which is the most common underlying disease in patients undergoing dialysis and with podocyte injury, remains unclear. Here, we investigated the therapeutic effect of enhanced GM3 expression via VPA on podocyte injury using streptozotocin-induced diabetic nephropathy model mice. Administration of VPA clearly decreased levels of albuminuria and glomerular lesions and inhibited the loss of podocytes and expansion in the mesangial area. Furthermore, we found that albuminuria levels in patients with diabetic nephropathy inversely correlate with the expression of GM3 in podocytes. These results indicate that maintaining GM3 expression in podocytes by administration of VPA may be effective in treating not only podocyte injury, such as MCD and FSGS, but also the late stage of diabetic nephropathy.

Quercetin Mitigates Diabetic Nephropathy in Rats via Keap1/Nrf2/HO-1 Signaling Pathway

A severe diabetic complication, diabetic nephropathy, progresses to terminal kidney disease. A chronic hyperglycemia-related excess of reactive oxygen species results in the advancement of diabetes complications. Through streptozotocin-induced diabetic nephropathy in rats, the present study investigated Quercetin’s renoprotective effect by upregulating nuclear factor-erythroid-related factor 2 (Nrf2) to cope with oxidative stress. During eight weeks study, daily food-water and weekly body weight were evaluated while biochemical, antioxidant parameters and genetic expression (Nrf2, Hemeoxygenease-1, Nuclear factor kappa B, Interlukin-6, and Caspase-3) were assessed at the end. The outcomes were interpreted using ANOVA, and the significance was determined using Dunnett’s test. Quercetin treatment for eight weeks significantly controlled hyperglycemia, dyslipidemia, and downregulated inflammatory activators NFκB, IL-6, and Caspase-3. The significant upregulation of Nrf2 gene expression reduced oxidative damage by promoting Antioxidant response elements and initiating downstream cascade (HO-1 and antioxidant enzymes). The results are supported by histopathology. Experimental evidence suggests that Quercetin can fight metabolic disorders and their related microvascular diseases by activating Nrf2.

Nephroprotective Potential of Sphaeranthus indicus Linn Extract against Hyperglycemia and Dyslipidemia in Streptozotocin-Induced Diabetic Nephropathy

Abstract Objective This study was aimed at determining the nephroprotective potential of Sphaeranthus indicus Linn methanol extract (SME) against hyperglycemia and dyslipidemia in streptozotocin (STZ)-induced diabetic nephropathy (DNP) in adult Wistar albino rats. Materials and Methods Following STZ-induced diabetes, adult albino Wistar rats of either sex with serum glucose level more than 250 mg/dL were chosen and randomized into six groups (n = 6 rats per group) and received the treatment as follows: Group I: Normal nondiabetic (ND) rats received a single intraperitoneal dose of citrate buffer in the same volume as STZ and 1% (w/v) carboxymethyl cellulose (CMC) per os (po), group II: diabetic (STZ) control rats received oral dosage of 1% (w/v) CMC, group III, IV and V: STZ + SME treated rats received a suspension of SME (100, 200, and 400 mg/kg, po) in 1% (w/v) CMC, and group VI: STZ + MET treated rats received metformin (500 mg/kg, po) as suspension in 1% (w/v) CMC. From 28th day to the 56th day of STZ injection, SME and MET were given for 28 days in the form of freshly prepared suspension. The impact of STZ-induced DNP was analyzed through the estimation of body weight, serum glucose, and hemoglobin A1c levels, renal functional parameters, the serum lipid profile, oxidative stress markers, and analysis of renal histoarchitecture. Result Diabetic (STZ) control rats showed significant alterations in body weight, serum glucose and hemoglobin A1c levels, renal functional parameters, the serum lipid profile, oxidative stress markers, and renal histoarchitecture in contrast to normal ND rats. SME and MET treatment significantly reduced hyperglycemia-induced enhanced lipid profile and oxidative stress, normalized renal functional parameters, and restored renal histoarchitecture by reducing vacuolar degeneration of renal tubules in contrast to diabetic (STZ) control rats. These findings were attributed to SME's efficacy in DNP. Conclusion In STZ-sensitized diabetic rats, SME retarded the progress of nephropathy. The observed nephroprotective potential of SME is ascribed to its hypoglycemic, hypolipidemic, and antioxidant activities.

Effectiveness of analog of Humanin in ameliorating streptozotocin-induced diabetic nephropathy in Sprague Dawley rats

Diabetes mellitus (DM) is associated with numerous complications, including nephropathy, which principally occur due to hyperglycemia-induced oxidative stress and inflammation. Humanin (HN), a novel peptide generated from mitochondria, has anti-oxidant and anti-inflammatory potential as observed in different disease models. However, role of HN in diabetic nephropathy (DN) has not yet been explored. This study aimed to evaluate biochemical and molecular aspects of the effects of HN analog, Humanin-glycine ([S14G]-humanin) on streptozotocin (STZ)-induced rat model of DN. Ninety Sprague Dawley (SD) rats were randomly segregated into three groups – A (control), B (disease control) and C (treatment). DM type-I was induced in group B and C via single intra-peritoneal dose of STZ (45 mg/Kg). Seven days following STZ injection, rats were deemed diabetic if their blood glucose level was > 250 mg/dL. Subsequently, diabetic rats in group C were injected with [S14G]-humanin intra-peritoneally (0.4 mg/Kg/day) for sixteen weeks. Biochemical analysis revealed that diabetic rats had markedly elevated levels of serum glucose, creatinine, BUN, TNF-α, and kidney tissue SOD. Whereas, significant decline was detected in serum insulin and albumin levels. All these parameters were significantly reversed in group C after administering [S14G]-humanin. Moreover, qRT-PCR analysis displayed up-regulation of pro-inflammatory (IL-18, IL-6, IL-1α, IL-1β, TNF-α) and down-regulation of anti-inflammatory cytokines (IL-10, IL-1RN, IL-4) in diabetic rats (group B). [S14G]-humanin treatment significantly reversed the expression of IL-18 and IL-1α, however, change in relative expression of IL-6, IL-1β, TNF-α and anti-inflammatory cytokines was insignificant (group C). Conclusively, the findings of this study depicted potential therapeutic role of [S14G]-humanin in pre-clinical rodent model of DN.

Heparanase-2 protein and peptides have a protective effect on experimental glomerulonephritis and diabetic nephropathy.

Introduction: The endothelial glycocalyx degrading enzyme heparanase-1 (HPSE1) is a major contributor to kidney diseases, such as glomerulonephritis and diabetic nephropathy. Therefore, inhibition of HPSE1 could be an interesting therapeutic strategy to treat glomerular diseases. A possible HPSE1 inhibitor is heparanase-2 (HPSE2) because HPSE2 is a structural homolog of HPSE1 without enzymatic activity. The importance of HPSE2 has been recently demonstrated in HPSE2-deficient mice, since these mice developed albuminuria and died within a few months after birth. We postulate that inhibition of HPSE1 activity by HPSE2 is a promising therapeutic strategy to target albuminuria and resulting renal failure. Methods: First, we evaluated the regulation of HPSE2 expression in anti-GBM and LPS-induced glomerulonephritis, streptozotocin-induced diabetic nephropathy, and adriamycin nephropathy by qPCR and ELISA. Second, we measured the HPSE1 inhibiting capacity of HPSE2 protein and 30 different HPSE2 peptides and assessed their therapeutic potential in both experimental glomerulonephritis and diabetic nephropathy using kidney function and cortical mRNA expression of HPSE1 and cytokines as outcome parameters. Results: HPSE2 expression was downregulated under inflammatory and diabetic conditions, whereas this effect on HPSE2 expression was absent with HPSE1 inhibition and in HPSE1-deficient mice. Both HPSE2 protein and a mixture of the three most potent HPSE1 inhibitory HPSE2 peptides could prevent LPS and streptozotocin induced kidney injury. Discussion: Taken together, our data suggest a protective effect of HPSE2 in (experimental) glomerular diseases and support the therapeutic potential of HPSE2 as HPSE1 inhibitor in glomerular diseases.

Local anaesthetic procaine derivatives protect rat against diabetic nephropathy via inhibition of DPP-4, inflammation and oxidative stress.

Diabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine-embedded thiazole-pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)-4, -8, and - 9 enzyme subtypes, where they selectively and potently inhibit DPP-4 as compared to other subtypes. The top three ranked DPP-4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF-ĸB transcription. Among these three, compound 8i was identified as the most potent NF-ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin-induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF-α, IL-1β and IL-6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine-embedded thiazole-pyrazole compounds as a novel class of agent against diabetic nephropathy.

Evaluation of Sida cordifolia and Sida rhombifolia extracts in a rat model of streptozotocin-induced diabetic nephropathy.

Sida cordifolia and Sida rhombifolia are regarded as useful herbs as they have been shown to be effective, inexpensive and harmless in the prevention of diabetes, and are recognized as valuable therapeutic substances. The purpose of this study was to assess the effect of S. cordifolia and S. rhombifolia in the treatment of diabetic nephropathy using a rat model. Extracts of S. cordifolia and S. rhombifolia were obtained using the Soxhlet method. The hydroalcoholic extract solvent was used in the following proportions: 70:30, 50:50 and 80:20. The 80:20 hydroalcoholic extract was observed to be the most potent. The inhibitory effects of the extract were determined using the α-amylase assay. The most potent extract also underwent total flavonoid, phenolic and free radical scavenging tests, and was incorporated into an animal study. Diabetes was induced in rats by administering nicotinamide (NAD; 230 mg/kg) and streptozotocin (STZ; 65 mg/kg) intraperitoneally. In addition to a standard control of pioglitazone, the rats received extract dosages of 100 mg/kg/day or 200 mg/kg/day. Body weight, blood glucose, glycated hemoglobin (HbA1c), blood urea nitrogen (BUN), serum albumin, serum creatinine, homeostatic model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance were assessed at various time points. The animals also underwent histopathological examination to observe alterations induced by the treatment. Sida cordifolia was the most successful in lowering blood glucose and HbA1c levels. Renal function indices and antioxidant enzyme levels were regained in a dose-dependent manner. Furthermore, S. cordifolia (200 mg/kg/day) extract, similar to pioglitazone, inhibited the production of advanced glycation byproducts by the kidney. The effects of various S. cordifolia and S. rhombifolia extracts on rats with diabetic nephropathy were observed. Sida cordifolia may be further explored for the treatment of diabetic nephropathy and, due to its diverse nature, may be utilized for the treatment of a wide range of diseases, as it provided more significant findings.

Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy.

This study assessed the efficacy of INV-202, a novel peripherally restricted cannabinoid type-1 receptor (CB1R) inverse agonist, in a streptozotocin-induced type-1 diabetes nephropathy mouse model. Diabetes was induced in 8-week-old C57BL6/J male mice via intraperitoneal injection of streptozotocin (45 mg/kg/day for 5 days); nondiabetic controls received citrate buffer. Diabetic mice were randomized to 3 groups based on blood glucose, polyuria, and albuminuria, and administered daily oral doses for 28-days of INV-202 at 0.3 or 3 mg/kg or vehicle. INV-202 did not affect body weight but decreased kidney weight compared with the vehicle group. While polyuria was unaffected by INV-202 treatment, urinary urea (control 30.77 ± 14.93; vehicle 189.81 ± 31.49; INV-202 (0.3 mg/kg) 127.76 ± 20; INV-202 (3 mg/kg) 93.70 ± 24.97 mg/24h) and albumin (control 3.06 ± 0.38; vehicle 850.08 ± 170.50; INV-202 (0.3 mg/kg) 290.65 ± 88.70; INV-202 (3 mg/kg) 111.29 ± 33.47 µg/24h) excretion both decreased compared with vehicle-treated diabetic mice. Compared with the vehicle group, there was a significant improvement in the urinary albumin to creatinine ratio across INV-202 groups. Regardless of the dose, INV-202 significantly reduced angiotensin II excretion in diabetic mice. The treatment also decreased Agtr1a renal expression in a dose-dependent manner. Compared with nondiabetic controls, the glomerular filtration rate was increased in the vehicle group and significantly decreased by INV-202 at 3 mg/kg. While the vehicle group showed a significant loss in the mean number of podocytes per glomerulus, INV-202 treatment limited podocyte loss in a dose-dependent manner. Moreover, in both INV-202 groups, expression of genes coding for podocyte structural proteins nephrin (Nphs1), podocin (Nphs2), and podocalyxin (Pdxl) were restored to levels similar to nondiabetic controls. INV-202 partially limited the proximal tubular epithelial cell (PTEC) hyperplasia and normalized genetic markers for PTEC lesions. INV-202 also reduced expression of genes contributing to oxidative stress (Nox2, Nox4, and P47phox) and inflammation (Tnf). In addition, diabetes-induced renal fibrosis was significantly reduced by INV-202. INV-202 reduced glomerular injury, preserved podocyte structure and function, reduced injury to PTECs, and ultimately reduced renal fibrosis in a streptozotocin-induced diabetic nephropathy mouse model. These results suggest that INV-202 may represent a new therapeutic option in the treatment of diabetic kidney disease.

Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2.

The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf-null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen-inducible (TAM-inducible) c-Maf-knockout mice (c-Maffl/fl; CAG-Cre-ERTM mice named "c-MafΔTAM") with those of c-Maffl/fl control mice, 10 days after TAM injection [TAM(10d)]. In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin, 4 weeks before TAM injection. c-MafΔTAM mice displayed primary glycosuria caused by sodium-glucose cotransporter 2 (Sglt2) and glucose transporter 2 (Glut2) downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the potentially unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.