Therapeutic effects of lisinopril and empagliflozin in a mouse model of hypertension-accelerated diabetic kidney disease

2021 ◽  
Author(s):  
Mette Viberg Østergaard ◽  
Thomas Secher ◽  
Michael Christensen ◽  
Casper Gravesen Salinas ◽  
Urmas Roostalu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
Synergistic Effects ◽  
Standard Of Care ◽  
Therapeutic Interventions ◽  
Therapeutic Effects ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Control Disease

Hypertension is a critical comorbidity for progression of diabetic kidney disease (DKD). To facilitate development of novel therapeutic interventions with the potential to control disease progression, there is a need to establish translational animal models that predict treatment effects in human DKD. The present study aimed to characterize renal disease and outcomes of standard of medical care in a mouse model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) db/db mice. Five weeks after single AAV administration and four weeks after UNx, female db/db UNx-ReninAAV mice received (PO, QD) vehicle, lisinopril (40 mg/kg), empagliflozin (20 mg/kg) or combination treatment for 12 weeks (n=17 per group). Untreated db/+ mice (n=8) and vehicle-dosed db/db UNx-LacZAAV mice (n=17) served as controls. Endpoints included plasma, urine and histomorphometric markers of kidney disease. Total glomerular numbers and individual glomerular volume was evaluated by whole-kidney 3D imaging analysis. db/db UNx-ReninAAV mice developed hallmarks of progressive DKD characterized by severe albuminuria, advanced glomerulosclerosis and glomerular hypertrophy. Lisinopril significantly improved albuminuria, glomerulosclerosis, tubulointerstitial injury and inflammation. While empagliflozin alone had no therapeutic effect on renal endpoints, lisinopril and empagliflozin exerted synergistic effects on renal outcomes. In conclusion, the db/db UNx-ReninAAV mouse demonstrates good clinical translatability with respect to the physiological and histological hallmarks of progressive DKD. Efficacy of standard of care to control hypertension and hyperglycemia provides proof-of-concept for testing novel drug therapies in the model.

scholarly journals Therapeutic Strategies for Diabetic Kidney Disease

Diabetology ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 31-35
Author(s):  
Keiichiro Matoba
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Intensive Therapy ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Hemodynamic Changes ◽  
Diabetic Kidney ◽  
Global Epidemic ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD) is a global epidemic leading to end-stage renal disease (ESRD) and susceptibility to cardiovascular disease, with few therapeutic interventions. A hallmark of DKD is the activation of the renin-angiotensin-aldosterone system and hemodynamic changes in glomerulus. Although intensive therapy with agents that targets those abnormalities lowers the risk of DKD progression, it does not completely abolish the risk of ESRD and cardiovascular events. Recent studies have illustrated the importance of renal inflammation, oxidative stress, and activated Rho-associated protein kinase (ROCK) signaling as essential pathogenesis for the development of DKD. In this commentary, these topics will be discussed.

scholarly journals The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease

2011 ◽  
Vol 21 (5) ◽  
pp. 285-291 ◽  
Author(s):  
Ariel Troib ◽  
Daniel Landau ◽  
Jack F. Youngren ◽  
Leonid Kachko ◽  
Ralph Rabkin ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Receptor Inhibition ◽  
Igf Receptor

Diabetic kidney disease in thedb/dbmouse

2003 ◽  
Vol 284 (6) ◽  
pp. F1138-F1144 ◽  
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.

scholarly journals Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong-Yuan Chang ◽  
Xiao-Qian Li ◽  
Min Chen ◽  
Ming-Hui Zhao
Keyword(s):  
Kidney Disease ◽  
Protective Effect ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Membrane Attack Complex ◽  
Sglt2 Inhibitors ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Proximal Tubular Epithelial Cells ◽  
Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

scholarly journals C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes

Diabetologia ◽  
2011 ◽  
Vol 54 (10) ◽  
pp. 2713-2723 ◽  
Author(s):  
F. Liu ◽  
H. Y. Chen ◽  
X. R. Huang ◽  
A. C. K. Chung ◽  
L. Zhou ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
C Reactive Protein ◽  
Diabetic Kidney ◽  
Reactive Protein

scholarly journals Gynostemma Pentaphyllum Ameliorates Lipid Metabolic Abnormalities in Diabetic Kidney Disease

2022 ◽  
Author(s):  
Pengrui Wang ◽  
Shouhai Jiao ◽  
Li Sun ◽  
Helin Sun ◽  
Cunzhi Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Protective Mechanisms ◽  
Diabetic Kidney ◽  
Gynostemma Pentaphyllum ◽  
Protein Protein Interaction

Abstract Background: Patients with diabetic kidney disease (DKD) were often accompanied with dislipidemia. Gynostemma pentaphyllum can ameliorate insulin resistance and reduce the synthesis of triglycerides and cholesterol, but the underlying mechanism is still unclear. Therefore, we used the network pharmacologic strategies to evaluate potential therapeutic effects and protective mechanisms of gynostemma pentaphyllum on diabetic kidney disease. Methods: Gynostemma pentaphyllum's potential targets were predicted using the TCMSP databases. The pathogenic factors involved in DKD and dislipidemia were screened by the OMIM and Gene Cards databases. The common targets of gynostemma pentaphyllum, DKD and dislipidemia were used to establish a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to explore the potential molecular pathways. Results: The key targets for the therapeutic effects of gynostemma pentaphyllum included IL-6, AKT1, VEGFA, PTGS2, CCL2 and CASP3. Enrichment analysis showed that the underlying mechanism were mainly the involved in inhibition of inflammatory response, negative regulation of apoptotic process and angiogenesis. TNF, PI3K-Akt, and HIF-1 signaling pathways were considered as the key pathways. Conclusion: Gynostemma pentaphyllum played a therapeutic role in DKD complicated with dislipidemia, mainly through influencing inflammation response, apoptosis and angiogenesis.

scholarly journals Mesangial matrix expansion in a novel mouse model of diabetic kidney disease associated with the metabolic syndrome

2020 ◽  
Vol 10 (2) ◽  
pp. e17-e17
Author(s):  
Elisabet Van Loon ◽  
Joseph Pierre Aboumsallem ◽  
Evelyne Lerut ◽  
Marija Bogojevic ◽  
Aleksandar Denic ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
Mesangial Matrix ◽  
Diabetic Kidney ◽  
The Metabolic Syndrome ◽  
Matrix Expansion

Effect of the Novel Compound SMTP‐27 in a Mouse Model of Diabetic Kidney Disease

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Keita Shibata ◽  
Erika Yasuda ◽  
Tomoka Nishinaga ◽  
Sarara Karasawa ◽  
Tomoaki Yamaguchi ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
The Novel ◽  
Diabetic Kidney
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