Pathophysiology Of Diabetic Nephropathy Research Articles

SRS 16-86 promotes diabetic nephropathy recovery by regulating ferroptosis.

Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM), and cell death plays an important role. Ferroptosis is a recently discovered type of iron-dependent cell death and one that is different from other kinds of cell death including apoptosis and necrosis. However, ferroptosis has not been described in the context of DN. This study explored the role of ferroptosis in DN pathophysiology and aimed to confirm the efficacy of the ferroptosis inhibitor SRS 16-86 on DN. Streptozotocin injection was used to establish the DM and DN animal models. To investigate the presence or occurrence of ferroptosis in DN, we assessed the concentrations of iron, reactive oxygen species and specific markers associated with ferroptosis in a rat model of DN. Additionally, we performed haematoxylin-eosin staining, blood biochemistry, urine biochemistry and kidney function analysis to evaluate the efficacy of the ferroptosis inhibitor SRS 16-86 in ameliorating DN. We found that SRS 16-86 could improve the recovery of renal function after DN by upregulating glutathione peroxidase 4, glutathione and system xc -light chain and by downregulating the lipid peroxidation markers and 4-hydroxynonenal. SRS 16-86 treatment could improve renal organization after DN. The inflammatory cytokines interleukin 1β and tumour necrosis factor α and intercellular adhesion molecule 1 were significantly decreased following SRS 16-86 treatment after DN. The results indicate that there is a strong connection between ferroptosis and the pathological mechanism of DN. The efficacy of the ferroptosis inhibitor SRS 16-86 in DN repair supports its use as a new therapeutic treatment for DN.

Fasting mimicking diet in diabetic mice partially preserves glomerular endothelial glycocalyx coverage, without changing the diabetic metabolic environment.

Intermittent fasting has become of interest for its possible metabolic benefits and reduction of inflammation and oxidative damage, all of which play a role in the pathophysiology of diabetic nephropathy. We tested in a streptozotocin (60 mg/kg)-induced diabetic apolipoprotein E knockout mouse model whether repeated fasting mimicking diet (FMD) prevents glomerular damage. Diabetic mice received 5 FMD cycles in 10 wk, and during cycles 1 and 5 caloric measurements were performed. After 10 wk, glomerular endothelial morphology was determined together with albuminuria, urinary heparanase-1 activity, and spatial mass spectrometry imaging to identify specific glomerular metabolic dysregulation. During FMD cycles, blood glucose levels dropped while a temporal metabolic switch was observed to increase fatty acid oxidation. Overall body weight at the end of the study was reduced together with albuminuria, although urine production was dramatically increased without affecting urinary heparanase-1 activity. Weight loss was found to be due to lean mass and water, not fat mass. Although capillary loop morphology and endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced together with the presence of UDP-glucuronic acid. Mass spectrometry imaging further revealed reduced protein catabolic breakdown products and increased oxidative stress, not different from diabetic mice. In conclusion, although FMD preserves partially glomerular endothelial glycocalyx, loss of lean mass and increased glomerular oxidative stress argue whether such diet regimes are safe in patients with diabetes.NEW & NOTEWORTHY Repeated fasting mimicking diet (FMD) partially prevents glomerular damage in a diabetic mouse model; however, although endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced in the presence of UDP-glucuronic acid. The weight loss observed was of lean mass, not fat mass, and increased glomerular oxidative stress argue whether such a diet is safe in patients with diabetes.

Farnesoid X receptor activation protects against renal fibrosis via modulation of β-catenin signaling

ObjectiveActivation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice. MethodsWe investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and β-catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and β-catenin was further verified. ResultsMice were fed by a 60% kcal fat diet for 20 weeks developed the typical traits of metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal β-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected β-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox-LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) β-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced α-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and α-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) β-catenin, nuclear translocation and β-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with β-catenin via the AF1 domain, and disrupt the assembly of the core β-catenin/TCF4 complex. ConclusionThese experimental data suggest that FXR activation, via modulating β-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.

Circulating hsa-miR-221 as a possible diagnostic and prognostic biomarker of diabetic nephropathy

BackgroundDiabetic nephropathy (DN), which is a chronic outcome of diabetes mellitus (DM), usually progresses to end-stage renal disease (ESRD). The DN pathophysiology, nevertheless, is not well-defined. Several miRNAs were reported to be either risk or protective factors in DN.Methods, and resultsThe present study sought to inspect the potential diagnostic and prognostic value of hsa-miR-221 in DN. The study included 200 participants divided into four groups: Group 1 (50 patients with DN), Group 2 (50 diabetic patients without nephropathy), Group 3 (50 nondiabetic patients with CKD), and Group 4 (50 healthy subjects as a control group). Patients in groups 1 and 3 were further classified based on the presence of macroalbuminuria and microalbuminuria. Hsa-miR-221 expression was measured by RT- qRT-PCR. DN patients had significantly elevated serum hsa-miR-221 levels than the other groups, while diabetic patients without nephropathy exhibited elevated levels compared to both nondiabetic patients with CKD, and the control group. The DN patients with macroalbuminuria revealed significantly higher mean values of hsa-miR-221 relative to the patients with microalbuminuria. Significant positive associations were observed in the DN group between serum hsa-miR-221 and fasting insulin, fasting glucose, HOMA IR, ACR, and BMI. The ROC curve analysis of serum hsa-miR-221 in the initial diagnosis of DN in DM revealed high specificity and sensitivity.ConclusionsIt is concluded that hsa-miR-221 has the potential to be a useful biomarker for prognostic and diagnostic purposes in DN.

Macrophage-derived exosomes promote activation of NLRP3 inflammasome and autophagy deficiency of mesangial cells in diabetic nephropathy

Dysfunction of mesangial cells plays a significant role in the glomerular lesions and is implicated in the pathophysiology of diabetic nephropathy (DN). Macrophages infiltration is the main pathological feature of DN, which can ultimately lead to renal inflammation. Recent studies suggest that the crosstalk between kidney resident cells and inflammatory cells influences the development of DN, and that controlling this crosstalk may help treat DN. Here, we found that DN mice appeared renal pathological damage, including dilation of mesangial matrix and significant infiltration of macrophages, accompanied by increased inflammatory response, NLRP3 inflammasome activation and autophagy deficiency. Additionally, mesangial cells internalized exosomes from high glucose (HG) treated macrophage, resulting the activation of inflammatory cytokines and NLRP3 inflammasome and deficiency of autophagy in vitro and in vivo. Moreover, C57BL/6 mice injected HG-stimulated macrophages-derived exosomes exhibited renal dysfunction and mesangial matrix expansion. Taken together, the present study demonstrated that mesangial cells responded to HG treated macrophage-derived exosomes by promoting the activation of NLRP3 inflammasome and autophagy deficiency, thereby participating in the development of DN.

Pediatric Diabetic Nephropathy: Novel Insights from microRNAs

Diabetic nephropathy (DN) represents the most common microvascular complication in patients with diabetes. This progressive kidney disease has been recognized as the major cause of end-stage renal disease with higher morbidity and mortality. However, its tangled pathophysiology is still not fully known. Due to the serious health burden of DN, novel potential biomarkers have been proposed to improve early identification of the disease. In this complex landscape, several lines of evidence supported a critical role of microRNAs (miRNAs) in regulating posttranscriptional levels of protein-coding genes involved in DN pathophysiology. Indeed, intriguing data showed that deregulation of certain miRNAs (e.g., miRNAs 21, -25, -92, -210, -126, -216, and -377) were pathogenically linked to the onset and the progression of DN, suggesting not only a role as early biomarkers but also as potential therapeutic targets. To date, these regulatory biomolecules represent the most promising diagnostic and therapeutic options for DN in adult patients, while similar pediatric evidence is still limited. More, findings from these elegant studies, although promising, need to be deeper investigated in larger validation studies. In an attempt to provide a comprehensive pediatric overview in the field, we aimed to summarize the most recent evidence on the emerging role of miRNAs in pediatric DN pathophysiology.

Therapeutic Potential of Resveratrol in Diabetic Nephropathy According to Molecular Signaling.

Diabetic nephropathy (DN), as a severe complication of diabetes mellitus (DM), is a crucial menace for human health and survival and remarkably elevates the healthcare systems' costs. Therefore, it is worth noting to identify novel preventive and therapeutic strategies to alleviate the disease conditions. Resveratrol, as a well-defined anti-diabetic/ antioxidant agent has capabilities to counteract diabetic complications. It has been predicted that resveratrol will be a fantastic natural polyphenol for diabetes therapy in the next few years. Accordingly, the current review aims to depict the role of resveratrol in the regulation of different signaling pathways that are involved in the reactive oxygen species (ROS) production, inflammatory processes, autophagy, and mitochondrial dysfunction, as critical contributors to DN pathophysiology. The pathogenesis of DN can be multifactorial; hyperglycemia is one of the prominent risk factors of DN development that is closely related to oxidative stress. Resveratrol, as a well-defined polyphenol, has various biological and medicinal properties, including anti-diabetic, anti-inflammatory, and anti-oxidative effects. Resveratrol prevents kidney damages that are caused by oxidative stress, enhances antioxidant capacity, and attenuates the inflammatory and fibrotic responses. For this reason, resveratrol is considered an interesting target in DN research due to its therapeutic possibilities during diabetic disorders and renal protection.

Taurine Ameliorates Apoptosis via AKT Pathway in the Kidney of Diabetic Rats.

Diabetic nephropathy is one of the major diabetic complications which has become the major cause of end-stage renal disease. It has been demonstrated that apoptosis induced by hyperglycemia is a critical factor in the pathophysiology of diabetic nephropathy. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The protective effect of taurine against apoptosis in diabetic kidney deserves to be explored. In the present study, mRNA expression of cysteinyl aspartate-specific proteinase-3 (caspase-3) and caspase-9 was examined, and the activity of caspase-3 was also detected as the marker of apoptosis. The expression of Bax and Bcl-2 was detected by Western blot. In addition, the level of total Akt and phosphorylated Akt (p-Akt) was measured. We found that caspase-3 and caspase-9 mRNA expression was decreased in diabetic kidney, which was recovered by taurine treatment. The activity of caspase-3 was increased in diabetic kidney, while the increased activity was significantly attenuated after taurine treatment. We also found that the expressions of Bax and Bcl-2 were disturbed in diabetic kidney, which were reversed by taurine treatment. The decrease of the p-Akt level was also prevented by taurine treatment. These results indicated that taurine-ameliorated apoptosis in diabetic kidney may be through activating of the Akt signaling pathway.

Selective decrease in alpha1-antitrypsin levels in diabetic retinopathy: Could the levels of it be playing a role in the pathophysiology of diabetic retinopathy?

Type 2 diabetes mellitus (T2DM) is known to induce inflammation and activation of neutrophils causing the release of neutrophil elastase (NE), a pro-inflammatory proteinase. The activity of NE is regulated by endogenous inhibitors alpha1-antitrypsin (α1-AT) and alpha2-macroglobulin (α2-MG). Disrupted proteolytic homeostasis in T2DM patients is one of the causes for vascular complications. This study was carried out for evaluating the levels of plasma NE, α1-AT, α2-MG and NE-α1-AT complex to understand their roles in the pathophysiology of diabetic nephropathy (DN) and diabetic retinopathy (DR). A total of 240 subjects (Control n=60, T2DM n=60, DN n=60 and DR n=60) were recruited after recording history, clinical examination and laboratory investigations. Retinopathy was confirmed by fundoscopy and nephropathy by urinary albumin excretion and serum creatinine levels. NE was measured using STANA. α1-AT, α2-MG and NE-α1-AT complex were estimated by ELISA. Baseline clinical and laboratory findings were confirmatory to the study groups. The mean elastase activity was higher (P<0.0005) in diabetes groups (T2DM=0.73±0.31, DN=0.87±0.35, DR=0.76±0.41) than controls (0.35±0.20). The levels of α1-AT were lower in DR (8.77±2.85) than DN (26.26±6.16) and T2DM (41.13±14.06) when juxtaposed with controls (122.95±25.71). The approximate fold decrease of α1-AT levels was 15 for DR and 4 for DN compared to controls. The levels of α2-MG were lowered in T2DM (167.29±30.45), DN (144.66±13.72) and DR (104.67±11.47) than controls (208.87±31.16). The NE-α1-AT complex levels were: controls (215.83±13.61), T2DM (98.85±23.85), DN (129.26±20.40) and DR (153.25±17.11). Homeostasis of NE, α1-AT and α2-MG is disrupted in T2DM, DN and DR. Strikingly reduced levels of α1-AT observed in DR are indicative of its possible role in the pathophysiology of retinopathy and emphasizes α1-AT as a plausible therapeutic target.

Acylcarnitines: Can They Be Biomarkers of Diabetic Nephropathy?

Diabetic nephropathy (DN), one of the most serious microvascular complications of diabetes mellitus (DM), may progress to end-stage renal disease (ESRD). Current biochemical biomarkers, such as urinary albumin excretion rate (UAER), have limitations for early screening and monitoring of DN. Recent studies have identified some metabolites as candidate biomarkers for early detection of DN. In this review, we summarize the role of dysregulated acylcarnitines (AcylCNs) in DN pathophysiology. Lower abundance of short- and medium-chain AcylCNs and higher long-chain AcylCNs often occurred in DM with normal albuminuria and microalbuminuria, compared with advanced stages of DN. The increase of long-chain AcylCNs was supposed to be an adaptive compensation in fat acids (FAs) oxidation in the early stage of DN. Conversely, the decrease of long-chain AcylCNs was due to incomplete oxidation of FAs in advanced stage of DN. Thus, AcylCNs may serve as sensitive biomarkers in predicting the risk of DN.

Circular RNAs in Diabetic Nephropathy: Updates and Perspectives.

Circular RNAs (circRNAs) are widespread endogenous transcripts lacking 5′-caps and 3′-polyadenylation tails. Their closed-loop structure confers exonuclease resistance and extreme stability. CircRNAs play essential roles in various diseases, including diabetes. Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease and is one of the most common complications of diabetes. CircRNAs are key in DN and therefore important for understanding DN pathophysiology and developing new therapeutic strategies. In the present review, we briefly introduce the characteristics and functions of circRNAs and summarize recent discoveries on how circRNAs participate in DN. Based on these advances, we suggest future perspectives for studying circRNAs in DN to improve DN treatment and management.

Chemotactic Cytokine Receptor 5 Genetic Polymorphism in Diabetic Nephropathy of the Type 2 Diabetes Mellitus

Background and Aim: The inflammatory process can be involved in the pathophysiology of diabetic nephropathy (DN). One of the cytokine receptors in the inflammatory process is Chemotactic Cytokine Receptor 5 (CCR5), whose genetic variation can affect the incidence of DN in several populations in the world. This study aims to determine the proportion of CCR5 gene polymorphisms with DN in type 2 diabetes mellitus patients in Bali. Method: This study used a case-control design in 144 DNA samples of patients with type 2 diabetes mellitus. They were examined for the polymorphisms of the CCR5 gene by PCR-RFLP and then analyzed using Chi-Square statistical test. The p value &lt;0.05 was significant. Results: The proportion of males more than females in subjects with diabetic nephropathy (p = 0.000). Duration of diabetes and systolic blood pressure were higher in subjects with diabetic nephropathy (p = 0.002; p = 0.002) respectively. The polymorphisms of the CCR5 gene did not differ significantly in subjects with and without diabetic nephropathy (p = 0.224). Conclusions: Gender, systolic blood pressure and duration of diabetes were associated with diabetic nephropathy, while CCR5 gene polymorphisms were not significantly associated with diabetic nephropathy in type 2 diabetes mellitus patients in Bali.

Naringenin alleviates hyperglycemia-induced renal toxicity by regulating activating transcription factor 4-C/EBP homologous protein mediated apoptosis.

Endoplasmic reticulum (ER) dysfunction plays a prominent role in the pathophysiology of diabetic nephropathy (DN). This study aimed to investigate the novel role of Naringenin (a flavanone mainly found in citrus fruits) in modulating ER stress in hyperglycemic NRK 52E cells and STZ/nicotinamide induced diabetes in Wistar rats. The results demonstrated that Naringenin supplementation downregulated the expression of ER stress marker proteins, including p-PERK, p-eIF2α, XBP1s, ATF4 and CHOP during hyperglycemic renal toxicity in vitro and in vivo. Naringenin abrogated hyperglycemia-induced ultrastructural changes in ER, evidencing its anti-ER stress effects. Interestingly, treatment of Naringenin prevented nuclear translocation of ATF4 and CHOP in hyperglycemic renal cells and diabetic kidneys. Naringenin prevented apoptosis in hyperglycemic renal cells and diabetic kidney tissues by downregulating expression of apoptotic marker proteins. Further, photomicrographs of TEM confirmed anti-apoptotic potential of Naringenin as it prevented membrane blebbing and formation of apoptotic bodies in hyperglycemic renal cells. Naringenin improved glucose tolerance, restored serum insulin level and reduced serum glucose level in diabetic rats evidencing its anti-hyperglycemic effects. Histopathological examination of kidney tissues also confirmed prevention of damage after 28days of Naringenin treatment in diabetic rats. Additionally, Naringenin diminished oxidative stress and improved antioxidant defense response during hyperglycemic renal toxicity. Taken together, our study revealed a novel role of Naringenin in ameliorating ER stress during hyperglycemic renal toxicity along with prevention of apoptosis, cellular and tissue damage. The findings suggest that prevention of ER stress can be exploited as a novel approach for the management of hyperglycemic nephrotoxicity.

Salusin‑β participates in high glucose‑induced HK‑2 cell ferroptosis in a Nrf‑2‑dependent manner.

Ferroptosis is critically involved in the pathophysiology of diabetic nephropathy (DN). As a bioactive peptide, salusin-β is abundantly expressed in the kidneys. However, it is unclear whether salusin-β participates in the pathologies of diabetic kidney damage by regulating ferroptosis. The present study found that high glucose (HG) treatment upregulated the protein expressions of salusin-β in a dose- and time-dependent manner. Genetic knockdown of salusin-β retarded, whereas overexpression of salusin-β aggravated, HG-triggered iron overload, antioxidant capability reduction, massive reactive oxygen species production and lipid peroxidation in HK-2 cells. Mechanistically, salusin-β inactivated nuclear factor erythroid-derived 2-like 2 (Nrf-2) signaling, thus contributing to HG-induced ferroptosis-related changes in HK-2 cells. Notably, the protein expression of salusin-β was upregulated by ferroptosis activators, such as erastin, RSL3, FIN56 and buthionine sulfoximine. Pretreatment with ferrostatin-1 (a ferroptosis inhibitor) prevented the upregulated protein expression of salusin-β in HK-2 cells exposed to HG. Taken together, these results suggested that a positive feedback loop between salusin-β and ferroptosis primes renal tubular cells for injury in diabetes.

LncRNA SOX2OT alleviates mesangial cell proliferation and fibrosis in diabetic nephropathy via Akt/mTOR-mediated autophagy

BackgroundAccumulating evidences have demonstrated that long non-coding RNAs (lncRNAs) are involved in the pathophysiology of diabetic nephropathy (DN). lncRNA SOX2OT plays an essential role in many diseases, including diabetes. Herein, we aim to investigate the underlying mechanism of lncRNA SOX2OT in DN pathogenesis.MethodsStreptozotocin-induced DN mouse models and high glucose-induced mouse mesangial cells were constructed to examine the expression pattern of lncRNA SOX2OT. The activation of autophagy was evaluated using immunohistochemistry, immunofluorescence and western blot analysis, respectively. SOX2OT overexpressing plasmid was applied to further verify the functional role of SOX2OT in DN pathogenesis. CCK-8 and EDU assays were performed to the proliferation of mesangial cells. Additionally, rapamycin, the inhibitor of mTOR signaling, was used to further clarify whether SOX2OT controls DN development through Akt/mTOR pathway.ResultslncRNA SOX2OT was markedly down-regulated both in streptozotocin-induced DN mice and high glucose-induced mouse mesangial cells. Moreover, overexpression of lncRNA SOX2OT was able to diminish the suppression of autophagy and alleviate DN-induced renal injury. Functionally, CCK-8 and EDU assays indicated that lncRNA SOX2OT overexpression significantly suppressed the proliferation and fibrosis of mesangial cells. Additionally, an obvious inhibition of Akt/mTOR was also observed with lncRNA SOX2OT overexpression, which was then further verified in vivo.ConclusionIn summary, we demonstrated that lncRNA SOX2OT alleviates the pathogenesis of DN via regulating Akt/mTOR-mediated autophagy, which may provide a novel target for DN therapy.

Immunohistochemical Expression Pattern of Mismatch Repair Genes in the Short-term Streptozotocin-induced Diabetic Rat Kidneys.

We studied the expression of mismatch repair genes (MMRs)-mutS protein homolog 2 (MSH2), PMS2, MutL homolog 1 (MLH1), and yH2AFX in diabetic rat kidneys. Streptozotocin-induced diabetes mellitus type 1 rat model (DM1) was used. Renal samples were collected 2 weeks and 2 months after DM1 induction and immunohistochemical expression of MMR genes in the renal cortex was analyzed. Diabetic animals showed lower MSH2 and higher yH2AFX kidney expression both 2 weeks and 2 months after DM1 induction. MLH1 expression significantly increased 2 weeks after DM1 induction (P<0.0001). The most substantial differences were observed in the period 2 weeks after induction, with lower MSH2 and higher MLH1 expression in the proximal convoluted tubules and distal convoluted tubules (DCT) of diabetic animals (P<0.001). yH2AFX expression significantly increased in the DCT of diabetic animals at both time points (P<0.001; P<0.01). PMS2 expression changed only in the glomeruli, where it significantly decreased 2 months after DM1 induction (P<0.05). We concluded that the most substantial changes in renal expression of MMRs are happening already 2 weeks after diabetes induction, predominantly in the proximal convoluted tubules and DCT. Moreover, DCT could have a critical role in the pathophysiology of diabetic nephropathy (DN) and might be a future therapeutic target in this condition. The obtained results point to the MMRs as a potential factor in the development and progression of DN, as well as the possible link between DN and renal carcinogenesis.

Plasma miR-193a-3p can be a potential biomarker for the diagnosis of diabetic nephropathy

Diabetic nephropathy is one of the most common microvascular complications in patients with diabetes. MicroRNA (miRNA, miR) is closely related to the formation, development and pathophysiology of diabetic nephropathy. We aimed to investigate whether miR-193a-3p could be used as a potential biomarker for the diagnosis of diabetic nephropathy. Plasma samples were collected from all the participants. TaqMan Low Density Array analysis was employed to obtain the miRNA profiles of plasma samples, and qRT-PCR was used to confirm the result. Receiver operating characteristic curves were employed to evaluate the specificity and sensitivity of miR-193a-3p for predicting diabetic nephropathy. The expression of miR-193a-3p and miR-320c was elevated and miR-27a-3p was decreased in diabetic nephropathy patients compared to patients with type 2 diabetes and healthy controls. We found that, in diabetic nephropathy patients, the elevated miR-193a-3p expression had a negative correlation with the level of evaluate glomerular filtration rate, while a positive correlation with the level of proteinuria. We further demonstrated that miR-193a-3p could be employed to distinguish patients with diabetic nephropathy. The Kaplan-Meier analysis showed that the high expression of miR-193a-3p significantly shortened the dialysis-free survival of diabetic nephropathy patients. In conclusion, miR-193a-3p is involved in diabetic nephropathy pathogenesis and may serve as a potentially novel diagnostic biomarker for diabetic nephropathy.

Nefropatia diabética: uma revisão integrativa da literatura

Objetivo: Compreender as atribuições causais da evolução e na fisiopatologia da Nefropatia diabética em pacientes com fatores de suscetibilidade. Métodologia: Trata-se de uma revisão integrativa da literatura. Foram realizadas buscas bases de dados eletrônicas Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde (BIREME), Biblioteca Virtual Scientific Eletronic Library Online (SciELO), US National Library of Medicine National Institutes of Health (PubMed). Os parâmetros de aptidão foram artigos científicos indexados no período de 2010 a 2020, registrados nos idiomas inglês, português ou espanhol. Resultados: Na elaboração da revisão integrativa foi observado na grande maioria dos artigos, a prevalência do tipo e força da evidência III, demostrando evidências intermediárias na relação da Nefropatia diabética e seus fatores de risco. A abordagem enfatizava a Nefropatia diabética avaliando a prevalência de seus fatores de risco e ressaltando a importância da detecção precoce destes aspectos associados, vislumbrando a qualidade de vida para a sociedade. Conclusão: Os dados obtidos por meio da revisão integrativa expõem que a Nefropatia Diabética está em constante prevalência e incidência, relacionada a diversos fatores de riscos das doenças crônicas aos hábitos alimentares, salientando a importância da detecção precoce destes aspectos relacionados com o intuito de evitar e protelar as complicações renais pelo Diabetes Mellitus e consequentemente diminuir as chances de morbidade e mortalidade em casos de progressão para a ND.

Triphala Ameliorates Nephropathy via Inhibition of TGF-β1 and Oxidative Stress in Diabetic Rats

Introduction: Advanced glycation end products, oxidative stress, and TGF-β expression play a crucial role in pathophysiology of diabetic nephropathy. Inhibition of oxidative stress and TGF-β expression by natural traditional medicines may give an economic and safe alternative treatment option. Triphala churna, a traditional medicine, has been proved to have potent antioxidant activity, and individual components of it have shown significant antidiabetic activity. Hence, the present study was designed to study the effect of Triphala churna in diabetic nephropathy in rats. Methods: Diabetes was induced in rats by administration of streptozotocin (55 mg/kg i.p.). Four weeks after induction of diabetes, the animals were treated with Triphala churna at the doses of 250, 500, and 1,000 mg/kg for next 4 weeks. Various biochemical and urine parameters such as glucose, creatinine, blood urea nitrogen (BUN), total protein, and albumin were assessed at the end of study. Creatinine clearance, BUN clearance, and glomerular filtration rate were determined. Oxidative stress parameters such as malondialdehyde, catalase, reduced glutathione, and superoxide dismutase were determined in kidney tissues. TGF-β1 expression was measured with ELISA, immunohistochemistry, and western blot techniques. Histopathology study was carried out with haemotoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome staining to determine histological changes. Results: Treatment with Triphala churna significantly improved urine parameters. Triphala churna treatment also improved plasma proteins, albumin, creatinine, and BUN levels. The oxidative stress was reduced in the kidney with the treatment of Triphala churna. Histopathological studies revealed that Triphala churna reduced kidney damage. Immunohistochemistry, ELISA, and western blotting study revealed that treatment with Triphala decreased the expression of TGF-β in kidney tissues. Conclusion: From the results, it can be concluded that Triphala churna has a significant nephroprotective effect because of its capability of inhibiting oxidative stress and TGF-β in diabetes.

Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors

SummaryDiabetic kidney disease (DKD) increases the risk for mortality and is the leading cause of end-stage renal disease. Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of DKD, especially in patients with advanced kidney disease. Herein, we show that in diabetes, mTORC1 activity is increased in renal proximal tubule cells (RPTCs) along with enhanced tubule-interstitial fibrosis; this is prevented by SGLT2i. Constitutive activation of mTORC1 in RPTCs induces renal fibrosis and failure and abolishes the renal-protective effects of SGLT2i in diabetes. On the contrary, partial inhibition of mTORC1 in RPTCs prevents fibrosis and the decline in renal function. Stimulation of mTORC1 in RPTCs turns on a pro-fibrotic program in the renal cortex, whereas its inhibition in diabetes reverses the alterations in gene expression. We suggest that RPTC mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis.