Revisiting Experimental Models of Diabetic Nephropathy

Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the prevalence of diabetic nephropathy (DN) has also increased, becoming the main cause of end-stage renal disease (ESRD) in the developed world. DN is characterized by albuminuria, a decline in glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, glomerular basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances in the last years have been able to modify and delay the natural course of diabetic kidney disease (DKD). Nevertheless, there is still an urgent need to characterize the pathways that are involved in DN, identify risk biomarkers and prevent kidney failure in diabetic patients. Rodent models provide valuable information regarding how DN is set and its progression through time. Despite the utility of these models, kidney disease progression depends on the diabetes induction method and susceptibility to diabetes of each experimental strain. The classical DN murine models (Streptozotocin-induced, Akita, or obese type 2 models) do not develop all of the typical DN features. For this reason, many models have been crossed to a susceptible genetic background. Knockout and transgenic strains have also been created to generate more robust models. In this review, we will focus on the description of the new DN rodent models and, additionally, we will provide an overview of the available methods for renal phenotyping.

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Diabetic kidney disease in thedb/dbmouse

AJP Renal Physiology ◽

10.1152/ajprenal.00315.2002 ◽

2003 ◽

Vol 284 (6) ◽

pp. F1138-F1144 ◽

Cited By ~ 267

Author(s):

Kumar Sharma ◽

Peter McCue ◽

Stephen R. Dunn

Keyword(s):

Diabetic Nephropathy ◽

Kidney Disease ◽

Mouse Model ◽

Renal Disease ◽

Mouse Models ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Matrix Expansion ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

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Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

International Journal of Molecular Sciences ◽

10.3390/ijms21113798 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3798 ◽

Cited By ~ 6

Author(s):

Sandra Rayego-Mateos ◽

José Luis Morgado-Pascual ◽

Lucas Opazo-Ríos ◽

Melania Guerrero-Hue ◽

Cristina García-Caballero ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Intracellular Signaling ◽

Experimental Models ◽

Diabetic Patients ◽

Beneficial Effects ◽

Number Of Patients ◽

Close Relationship ◽

Stage Renal Disease ◽

End Stage ◽

Inflammatory Molecules

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

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New Experimental Models of Diabetic Nephropathy in Mice Models of Type 2 Diabetes: Efforts to Replicate Human Nephropathy

Experimental Diabetes Research ◽

10.1155/2012/616313 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 40

Author(s):

María José Soler ◽

Marta Riera ◽

Daniel Batlle

Keyword(s):

Diabetic Nephropathy ◽

Kidney Disease ◽

Substantial Effect ◽

Experimental Models ◽

Characteristic Features ◽

Stage Renal Disease ◽

End Stage ◽

Glomerular Tuft ◽

Human Nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. The use of experimental models of DN has provided valuable information regarding many aspects of DN, including pathophysiology, progression, implicated genes, and new therapeutic strategies. A large number of mouse models of diabetes have been identified and their kidney disease was characterized to various degrees. Most experimental models of type 2 DN are helpful in studying early stages of DN, but these models have not been able to reproduce the characteristic features of more advanced DN in humans such as nodules in the glomerular tuft or glomerulosclerosis. The generation of new experimental models of DN created by crossing, knockdown, or knockin of genes continues to provide improved tools for studying DN. These models provide an opportunity to search for new mechanisms involving the development of DN, but their shortcomings should be recognized as well. Moreover, it is important to recognize that the genetic background has a substantial effect on the susceptibility to diabetes and kidney disease development in the various models of diabetes.

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Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽

10.3390/biomedicines9050457 ◽

2021 ◽

Vol 9 (5) ◽

pp. 457

Author(s):

Kyeong-Seok Kim ◽

Jin-Sol Lee ◽

Jae-Hyeon Park ◽

Eun-Young Lee ◽

Jong-Seok Moon ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Early Stage ◽

Kidney Injury ◽

Diabetic Patients ◽

High Morbidity ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Zucker Diabetic Fatty Rats ◽

Kidney Injury Molecule 1 ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

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Podocalyxin as an early marker predicting diabetic nephropathy and its correlation with stages of diabetic nephropathy in type two diabetic patients

QJM ◽

10.1093/qjmed/hcab100.097 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Salah El-Din A Shelbaya ◽

Hanan M Ali ◽

Rana H Ibrahim ◽

Nourhan Safwat Sawirs

Keyword(s):

Diabetic Nephropathy ◽

Renal Disease ◽

End Stage Renal Disease ◽

Control Group ◽

Diabetic Patients ◽

Type 2 Dm ◽

Stage Renal Disease ◽

End Stage ◽

Positive Significant Correlation

Abstract Background Nephropathy, a major complication of diabetes, is the leading cause of end-stage renal disease. Early identification of nephropathy in diabetes patients is crucial because it creates opportunity for preventing the incidence of DN and/or even slows down the process of end-stage renal disease attributed to diabetes. Human podocytes (Pods) have been demonstrated to be functionally and structurally injured in the natural history of diabetic nephropathy. Aim of the Work To evaluate the possible association between the urinary podocalyxin levels and severity and grade of diabetic nephropathy and to use urinary podocalyxin as a non-invasive marker for early stage of diabetic nephropathy in type 2 DM. Patients and Methods We collected 60 known clinically and biochemically type 2 diabetic patients.20 diabetic patients with no evidence of diabetic nephropathy, 20 patients diagnosed as diabetic nephropathy in microalbuminuria stages and 20 patients diagnosed as diabetic nephropathy in macroalbuminuria stages from Ain Shams University hospitals between April and December 2018 and 20 apparently healthy volunteers will included as a control group. Results Urinary PCX was significantly higher in patients group compared to control group. Urinary PCX was significantly higher in microalbuminuric group than in normoalbuminuric group and higher in macroalbuminuric group than in microalbuminuric group. There was a positive significant correlation between FBS, 2HrPP, HBA1C and urinary PCX. There was a positive significant correlation between s.create and urinary PCX. There was a positive significant correlation between ACR and urinary PCX. Conclusion Urinary podocalyxin seems to be beneficial as an early marker for early stages of diabetic nephropathy in type 2 DM patients.

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Diabetic nephropathy as a cause of end-stage renal disease in Egypt: a six-year study

Eastern Mediterranean Health Journal ◽

10.26719/2004.10.4-5.620 ◽

2004 ◽

Vol 10 (4-5) ◽

pp. 620-626 ◽

Cited By ~ 1

Author(s):

A. Afifi ◽

M. El Setouhy ◽

M. El Sharkawy ◽

M. Ali ◽

H. Ahmed ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Renal Disease ◽

End Stage Renal Disease ◽

Large Scale ◽

Cross Sectional Study ◽

Diabetic Patients ◽

Cross Sectional ◽

Stage Renal Disease ◽

End Stage ◽

Esrd Patients

The prevalence of diabetic nephropathy as a cause of end-stage renal disease [ESRD] in Egypt has been examined in small cross-sectional studies, with conflicting results. The need for a large-scale study prompted us to perform this 6-year multiple cross-sectional study. A sample of ESRD patients enrolled in the Egyptian renal data system was evaluated during the period 1996-2001 for the prevalence of diabetic nephropathy. Prevalence gradually increased from 8.9% in 1996, to 14.5% in 2001. The mean age of patients with diabetic nephropathy was significantly higher than that of patients with ESRD from other causes. Mortality was also significantly higher in diabetic patients with ESRD

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Association of HbA1C Variability and Renal Progression in Patients with Type 2 Diabetes with Chronic Kidney Disease Stages 3–4

International Journal of Molecular Sciences ◽

10.3390/ijms19124116 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4116 ◽

Cited By ~ 12

Author(s):

Mei-Yueh Lee ◽

Jiun-Chi Huang ◽

Szu-Chia Chen ◽

Hsin-Ying Chiou ◽

Pei-Yu Wu

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Lower Risk ◽

Glycosylated Hemoglobin ◽

Diabetic Patients ◽

Patients With Diabetes ◽

Cox Analysis ◽

Stage Renal Disease ◽

End Stage ◽

Hba1c Variability

Little is known about the predictive value of glycosylated hemoglobin (HbA1C) variability in patients with advanced chronic kidney disease (CKD). The aim of this study was to investigate whether HbA1C variability is associated with progression to end-stage renal disease in diabetic patients with stages 3–5 CKD, and whether different stages of CKD affect these associations. Three hundred and eighty-eight patients with diabetes and stages 3–5 CKD were enrolled in this longitudinal study. Intra-individual HbA1C variability was defined as the standard deviation (SD) of HbA1C, and the renal endpoint was defined as commencing dialysis. The results indicated that, during a median follow-up period of 3.5 years, 108 patients started dialysis. Adjusted Cox analysis showed an association between the highest tertile of HbA1C SD (tertile 3 vs. tertile 1) and a lower risk of the renal endpoint (hazard ratio = 0.175; 95% confidence interval = 0.059–0.518; p = 0.002) in the patients with an HbA1C level ≥ 7% and stages 3–4 CKD, but not in stage 5 CKD. Further subgroup analysis showed that the highest two tertiles of HbA1C SD were associated with a lower risk of the renal endpoint in the group with a decreasing trend of HbA1C. Our results demonstrated that greater HbA1C variability and a decreasing trend of HbA1C, which may be related to intensive diabetes control, was associated with a lower risk of progression to dialysis in the patients with stages 3–4 CKD and poor glycemic control (HbA1c ≥ 7%).

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Changes of MicroRNA-377 in Diabetic Nephropathy

QJM ◽

10.1093/qjmed/hcaa052.052 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

H A Elshinnawy ◽

C R Kamel ◽

M H A Elkeleng

Keyword(s):

Diabetic Nephropathy ◽

Diabetic Patients ◽

Ckd Stage ◽

Significant Difference ◽

Group 3 ◽

Group 2 ◽

Stage Renal Disease ◽

End Stage ◽

Stage 1

Abstract Background as one of the most important long term complications of diabetes, Diabetic nephropathy is the major cause of end stage renal disease and high mortality. Purpose to identify the pattern of microRNA-377 changes specific for diabetic nephropathy in diabetic patients and in patients with chronic kidney disease of different etiology. Patients and Methods the study was conducted from 2016 to 2018, included 50 patients for analysis of MicroRNA-377 and its control gene U18 at El Demrdash Hospital Ain shams university and Quessena Hospital El Monfia. The miRNA-U18 was analyzed for normalization of correction ratio. Results the results of our research found that the highest median IQR of miR-377 was significantly present in DN stage 1&2 and the lowest median IQR was significantly present in CKD stage 1&2, and there was significant difference between group 1 (DN stage 1&2) versus group 2 (DN stage 3&4), group 3 (Diabetics without nephropathy) and all stages of CKD. Conclusion in diabetic nephropathy stage 1&2, serum miR-377 was highly significant increased more than diabetics without nephropathy, diabetic nephropathy stage 3&4 and all satges of CKD.

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Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2016/5749857 ◽

2016 ◽

Vol 2016 ◽

pp. 1-18 ◽

Cited By ~ 28

Author(s):

Guang-dong Sun ◽

Chao-yuan Li ◽

Wen-peng Cui ◽

Qiao-yan Guo ◽

Chang-qing Dong ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Diabetic Patients ◽

Protective Effects ◽

Chronic Complications ◽

Poor Treatment ◽

Stage Renal Disease ◽

End Stage ◽

And Control

Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20–40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN.

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Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge

Frontiers in Medicine ◽

10.3389/fmed.2021.654557 ◽

2021 ◽

Vol 8 ◽

Author(s):

Michele Provenzano ◽

Maria Chiara Pelle ◽

Isabella Zaffina ◽

Bruno Tassone ◽

Roberta Pujia ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Hypoglycemic Agents ◽

Renal Outcome ◽

Diabetic Patients ◽

Oral Hypoglycemic Agents ◽

Renal Protection ◽

Urinary Glucose ◽

Induce Weight Loss ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.

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