Corroborating Packer's Posit regarding Advantageous actions of SGLT2 hampering agents on Advantageous Cardiovascular Outcome: with Nutrient Deprivation Signaling/ Autophagic flux Posit in the Absence of SGLT2 Receptors in Heart: A Narrative Review

Abstract 

SGLT2- hampering agents generate an inimitable fashion ofadvantageous evolution/properties of propagating cardiomyopathy /nephropathy, having features of diminished oxidative /endoplasmic reticulum (ER) stress, mitochondrial health replacement, escalatedmitochondrial biogeneration, decreased proinflammatory /profibrotic pathways, and conservation of cellular/organ intactness/ viability. Considerable validation points that this canonical fashion of reactions might be explained by SGLT2- hampering agents actions in facilitating cellular housekeeping by escalating autophagic flux, which might be associatedwith actions of such agents for generating concomitant upregulation of nutrient deprivation signaling(NDS) and downregulation of nutrient surplus(NS) signaling, the way presenting by escalated expression /activity of AMP-activated protein kinase(AMPK), Sirtuins (SIRT1), SIRT3, SIRT6, Peroxisome Proliferator Activated Receptor γCoactivator -1α(PGC-1α) and diminished mammalian target of rapamycin (mTOR) activation .The unique cardioprotective / renoprotective SGLT2- hampering agents actions got ameliorated by particular hampering /knockdown of autophagy, AMPK and sirtuins. Proteomic evaluation of blood clinically, acquired during randomized controlled triasls this design of differentially escalated proteins is paralleled with these findings. Clinical studies further illustrated; SGLT2- hampering agents facilitate gluconeogenesis, ketogenesis, erythrocytosis and diminished uricemia, the emblem of NDS and the key statistical modulator of capacityof SGLT2- hampering agents for diminishing risk of HF and robustrenal processes. SGLT2- hampering agents effects of exaggerating autophagic flux is found in secluded cells/tissue not expressing SGLT2; thereby not exposed to altered glucose/ketones in their milieu and probably associated with these agents capacity ofdirectly binding sirtuins /mTOR. Altered renal/cardiovascular physiology/metabolismcan't be explained by the advantageous SGLT2- hampering agents actions in clinical scenario /experimental ones. The direct molecular SGLT2- hampering agents actions in secluded cells are paralleled with the belief that SGLT2 works as NS sensor, thereby its hampering causes NDS with its associated cytoprotective actions which can be attenuated by hampering/ knockdown of autophagy, AMPK and sirtuins. This corroborated Packers posit given in 2020, thus explaining the cardioprotective actions of them with lack of SGLT2R.

Key Words: SGLT2- hampering agents; nutrient deprivation signaling (NDS); autophagic flux. cardiorenal advantages