Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management

Abstract

Although advances in medical technology and health care have improved the early diagnosis and management for cardiorenal metabolic disorders, the prevalence of obesity, insulin resistance, diabetes, hypertension, dyslipidemia, and kidney disease remains high. Findings from numerous population-based studies, clinical trials, and experimental evidence have consolidated a number of theories for the pathogenesis of cardiorenal metabolic anomalies including resistance to the metabolic action of insulin, abnormal glucose and lipid metabolism, oxidative and nitrosative stress, endoplasmic reticulum (ER) stress, apoptosis, mitochondrial damage, and inflammation. Accumulating evidence has recently suggested a pivotal role for proteotoxicity, the unfavorable effects of poor protein quality control, in the pathophysiology of metabolic dysregulation and related cardiovascular complications. The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathways, two major although distinct cellular clearance machineries, govern protein quality control by degradation and clearance of long-lived or damaged proteins and organelles. Ample evidence has depicted an important role for protein quality control, particularly autophagy, in the maintenance of metabolic homeostasis. To this end, autophagy offers promising targets for novel strategies to prevent and treat cardiorenal metabolic diseases. Targeting autophagy using pharmacological or natural agents exhibits exciting new strategies for the growing problem of cardiorenal metabolic disorders.

P53/PANK1/miR‐107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high‐fat diet

“…Several factors are involved in the progression of IR induced by HFD including inflammation, excessive ROS, abnormal immune response, lipotoxicity and altered glycosylation . Recently, an important role for protein quality control, particularly autophagy, has been depicted in the maintenance of metabolic homeostasis . However, the mechanism underlying IR is far from clarified.…”

“…1,[24][25][26][27][28] Recently, an important role for protein quality control, particularly autophagy, has been depicted in the maintenance of metabolic homeostasis. 29 However, the mechanism underlying IR is far from clarified. Our data showed that the lipogenesis, lipid accumulation, lipid oxidation and gluconeogenesis in liver was inhanced induced by HFD, while the glycolysis was suppressed.…”

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

“…Mice with podocyte-specific deletion of autophagic regulators, such as class III PI3K vacuolar protein sorting 34 (Vps34) and the Atg5 gene, develop early proteinuria, progressive glomerulosclerosis, and renal failure [6]. Accordingly, autophagy is considered a potential therapeutic target for renal protection [8,9].Sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidylpeptidase-4 (DPP4) inhibitors are promising antidiabetic agents introduced into clinical practice in the last decade. The antihyperglycemic effect of SGLT2 inhibitors is mediated by increment of glucosuria, while DPP4 inhibitors realize their activity through an increase in the half-life of incretin hormones.…”

“…Mice with podocyte-specific deletion of autophagic regulators, such as class III PI3K vacuolar protein sorting 34 (Vps34) and the Atg5 gene, develop early proteinuria, progressive glomerulosclerosis, and renal failure [6]. Accordingly, autophagy is considered a potential therapeutic target for renal protection [8,9].…”

A Review on the Antioxidative and Prooxidative Properties of Luteolin

“…Cellular ROS are commonly generated through mitochondrial respiratory chain in most tissues. Steady-state ROS are maintained at nontoxic levels through various antioxidant and repair enzymes [2,5,6]. The delicate balance between oxidative stress and antioxidant defenses appears to play an essential role in cell survival, proliferation, and cell death [7,8].…”