Sacubitril/Valsartan treatment has differential effects in modulating diabetic kidney disease in db/db mice and KKAy mice when compared to valsartan treatment

2021 ◽  
Author(s):  
Komuraiah Myakala ◽  
Bryce Jones ◽  
Xiaoxin Wang ◽  
Moshe Levi
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Renal Protection ◽  
Diabetic Kidney ◽  
Renin Angiotensin ◽  
Kkay Mice ◽  
Neprilysin Inhibitor ◽  
Angiotensin Blockade

Although renin-angiotensin blockade has shown the beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug sacubitril/valsartan (Sac/Val), a combination of angiotensin II receptor blocker valsartan and neprilysin inhibitor prodrug sacubitril, has been shown more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study we tested the effects of Sac/Val in the diabetic kidney disease. We administered Sac/Val or valsartan to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3-month treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Valsartan shared the similar improvement but to a lesser degree in some parameters compared to Sac/Val. Sac/Val but not valsartan decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on anti-oxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self DNA activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by Sac/Val or valsartan treatment. Present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease and its effectiveness could be better than valsartan alone.

scholarly journals Present and Future in the Treatment of Diabetic Kidney Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Borja Quiroga ◽  
David Arroyo ◽  
Gabriel de Arriba
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Angiotensin Ii Receptor ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Diabetic Kidney ◽  
Renin Angiotensin ◽  
Renin Inhibitors

Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade.

scholarly journals MMP-10 is Increased in Early Stage Diabetic Kidney Disease and can be Reduced by Renin-Angiotensin System Blockade

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
José María Mora-Gutiérrez ◽  
José Antonio Rodríguez ◽  
María A. Fernández-Seara ◽  
Josune Orbe ◽  
Francisco Javier Escalada ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Renin Angiotensin System ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Angiotensin System ◽  
Diabetic Kidney ◽  
Renin Angiotensin

AbstractMatrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD.

scholarly journals Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease

2020 ◽  
Vol 35 (Supplement_1) ◽  
pp. i13-i23 ◽  
Author(s):  
Jose Luis Górriz ◽  
Juan F Navarro-González ◽  
Alberto Ortiz ◽  
Ander Vergara ◽  
Julio Nuñez ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Safety Management ◽  
Blood Glucose Control ◽  
European Medicines Agency ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Renin Angiotensin ◽  
Sodium Glucose Cotransporter

Abstract Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin–angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate &gt;45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin–angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication.

scholarly journals Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations

2020 ◽  
Vol 33 (5) ◽  
pp. 949-963
Author(s):  
Giovanna Leoncini ◽  
Francesca Viazzi ◽  
Salvatore De Cosmo ◽  
Giuseppina Russo ◽  
Paola Fioretto ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Blood Pressure Control ◽  
Therapeutic Approach ◽  
Diabetic Kidney Disease ◽  
Blood Pressure Reduction ◽  
Pressure Control ◽  
Renal Outcome ◽  
Renal Protection ◽  
Diabetic Kidney

Abstract Diabetic kidney disease (DKD) affects approximately one-third of patients with diabetes and taking into consideration the high cardiovascular risk burden associated to this condition a multifactorial therapeutic approach is traditionally recommended, in which glucose and blood pressure control play a central role. The inhibition of renin–angiotensin–aldosterone RAAS system represent traditionally the cornerstone of DKD. Clinical outcome trials have demonstrated clinical significant benefit in slowing nephropathy progression mainly in the presence of albuminuria. Thus, international guidelines mandate their use in such patients. Given the central role of RAAS activity in the pathogenesis and progression of renal and cardiovascular damage, a more profound inhibition of the system by the use of multiple agents has been proposed in the past, especially in the presence of proteinuria, however clinical trials have failed to confirm the usefulness of this therapeutic approach. Furthermore, whether strict blood pressure control and pharmacologic RAAS inhibition entails a favorable renal outcome in non-albuminuric patients is at present unclear. This aspect is becoming an important issue in the management of DKD since nonalbuminuric DKD is currently the prevailing presenting phenotype. For these reasons it would be advisable that blood pressure management should be tailored in each subject on the basis of the renal phenotype as well as related comorbidities. This article reviews the current literature and discusses potentials and limitation of targeting the RAAS in order to provide the greatest renal protection in DKD.

Potential of Renin-Angiotensin-Aldosterone System Modulations in Diabetic Kidney Disease: Old Players to New Hope!

2020 ◽  
Author(s):  
Vajir Malek ◽  
Sachin V. Suryavanshi ◽  
Nisha Sharma ◽  
Yogesh A. Kulkarni ◽  
Shrikant R. Mulay ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin Aldosterone System ◽  
Diabetic Kidney ◽  
Renin Angiotensin

SGLT-2 inhibitors in Diabetic Kidney Disease: What Lies Behind their Renoprotective Properties?

2019 ◽  
Vol 26 (29) ◽  
pp. 5564-5578 ◽  
Author(s):  
Panagiotis I. Georgianos ◽  
Maria Divani ◽  
Theodoros Eleftheriadis ◽  
Peter R. Mertens ◽  
Vassilios Liakopoulos
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Systemic Blood Pressure ◽  
Favorable Effect ◽  
Bibliographic Databases ◽  
Preclinical Studies ◽  
Renal Protection ◽  
Glucose Lowering ◽  
Diabetic Kidney ◽  
High Sodium

Background: Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensinaldosterone- system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD. Methods: A systematic literature search of bibliographic databases was conducted to identify preclinical studies and randomized trials evaluating the effects SGLT-2 inhibitors on DKD. Results: Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis. The renoprotective action of SGLT-2 inhibitors is strongly supported by human studies showing that these agents prevent the progression of albuminuria and retard nephropathy progression to ESRD. This beneficial effect of SGLT-2 inhibitors is not fully explained by their glucose-lowering properties. Attenuation of glomerular hyperfiltration and improvement in a number of surrogate risk factors, including associated reduction in systemic blood pressure, body weight, and serum uric acid levels may represent plausible mechanistic explanations for the cardio-renal protection offered by SGLT-2 inhibitors. Furthermore, the tubular cell metabolism seems to be altered towards a ketone-prone pathway with protective activities. Conclusion: SGLT-2 inhibition emerges as a novel therapeutic approach of diabetic with anticipated benefits towards cardio-renal risk reduction. Additional research efforts are clearly warranted to elucidate this favorable effect in patients with overt DKD.

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