Potential of Renin-Angiotensin-Aldosterone System Modulations in Diabetic Kidney Disease: Old Players to New Hope!
Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the renin-angiotensin-aldosterone system
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Potential of Renin-Angiotensin-Aldosterone System Modulations in Diabetic Kidney Disease: Old Players to New Hope! Vajir Malek, Sachin V. Suryavanshi, Nisha Sharma, Yogesh A. Kulkarni, Shrikant R. Mulay, and Anil Bhanudas Gaikwad
Contents 1 Introduction 2 The Renin-Angiotensin-Aldosterone System 3 The Pressor Arm of RAAS 3.1 Renin 3.2 Angiotensin-Converting Enzyme 3.3 Angiotensin II 3.4 Ang II Type 1 Receptor 4 The Pressor RAAS Inhibitors in DKD: The Old Players 4.1 Direct Renin Inhibitors 4.2 ACE Inhibitors 4.3 AT1 Receptor Blockers 4.4 Mineralocorticoid Receptor Antagonists 4.5 ACEi and ARB Combination Therapy 4.6 ARB or ACEi with Renin Inhibition 4.7 Hurdles for RAAS Inhibition in DKD 5 The Depressor Arm of RAAS 5.1 Angiotensin-Converting Enzyme 2: Nature’s ACEi 5.2 Angiotensin-(1-7) 5.3 Angiotensin II Type 2 Receptor 5.4 Mas Receptors 6 Modulation of the Depressor Arm of RAAS in DKD: A Better Alternative 6.1 ACE2 Activation 6.2 Ang-(1-7) Therapy 6.3 AT2 Receptor Modulations
V. Malek, N. Sharma, and A. B. Gaikwad (*) Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani, Rajasthan, India e-mail: [email protected] S. V. Suryavanshi and Y. A. Kulkarni Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai, India S. R. Mulay Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
V. Malek et al. 6.4 Mas Receptor Modulations 7 Neprilysin Inhibition as Add-On to RAAS Blockage 7.1 Vasopeptidase Inhibitor (Dual ACEi/NEPi) 7.2 Angiotensin Receptor Neprilysin Inhibitors (ARNi) 8 Novel Combination Therapies (Fig. 4) 8.1 Simultaneous AT1 Receptor Inhibition and AT2 Receptor Activation 8.2 Add-On Therapy of Ang-(1-7) with RAAS Inhibitors 8.3 Dual AT2 Receptor and ACE2 Activation 8.4 Mas Receptor Agonist and DRI Combination Therapies 8.5 Concurrent Renin and Neprilysin Inhibition 8.6 Add-On Therapy of NEPi with ACE2 Activation 8.7 Dual pGC-A and Mas Receptor Activators 9 Conclusion and Perspective References
Abstract Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the reninangiotensin-aldosterone system (RAAS) is key to the development and progression of DKD. Consequently, RAAS inhibition by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the first-line therapy for the clinical management of DKD. However, numerous clinical and preclinical evidences suggested that RAAS inhibition can only halt the progression of the DKD to a certain extent, and they are inadequate to cure DKD completely. Recent studies have improved understanding of the complexity of the RAAS. It consists of two counterregulatory arms, the deleterious pressor arm (ACE/angiotensin II/AT1 receptor axis) and the beneficial depressor arm (ACE2/angiotensin-(1-7)/Mas receptor axis). These advances have paved the way
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