Molecular pathophysiology of acute kidney injury: The role of sirtuins and their interactions with other macromolecular players

Abstract

Acute kidney injury (AKI), a rapid drop in kidney function, displays high mortality and morbidity, and its repeated or severe status can shift into chronic kidney disease or even end‐stage renal disease. How and which events cause AKI still is controversial. In addition, no specific therapies have emerged that can attenuate AKI or expedite recovery. Some central mechanisms including tubular epithelial cells injury, endothelial injury, renal cell apoptosis, and necrosis signaling cascades, and inflammation have been reported in the pathophysiology of AKI. However, the timing of the activation of each pathway, their interactions, and the hierarchy of these pathways remain unknown. The main molecular mechanisms that might be complicated in this process are the mitochondrial impairment and alteration/shifting of cellular metabolites (e.g., acetyl‐CoA and NAD+/NADH) acting as cofactors to alter the activities of many enzymes, for instance, sirtuins. Moreover, alteration of mitochondrial structure over the fusion and fission mechanisms can regulate cellular signaling pathways by modifying the rate of reactive oxygen species generation and metabolic activities. The aim of this review is to better understand the underlying pathophysiological and molecular mechanisms of AKI. In addition, we predicted the main other molecular players in interaction with sirtuins as energy/stresses monitoring proteins for the development of future approaches in the treatment or prevention of ischemic AKI.

Protective effects of mefunidone on ischemia-reperfusion injury/Folic acid-induced acute kidney injury

“…However, excessive apoptosis adversely affects the body ( Priante et al, 2019 ). Apoptosis of renal tubular epithelial cells is an important mechanism in IRI-induced nephropathy ( Li et al, 2021b ; Kim et al, 2021 ; Rahbar Saadat et al, 2021 ). Here, we revealed that mefunidone treatment significantly suppressed renal apoptosis induced by IRI using TUNEL staining and concluded that mefunidone can reduce the expression of the apoptotic marker cleaved-caspase3.…”

“…IRI is characterized by a short period of organ blood flow restriction followed by blood flow restoration, which initiates multiple cascades of destructive reactions ( Kar et al, 2020 ). Due to the lack of effective treatment, AKI can gradually develop into chronic kidney disease (CKD), which is also easy to combine with other diseases, resulting in serious consequences ( Martina et al, 2016 ; Rahbar Saadat et al, 2021 ). Despite a steady increase in the incidence of IRI-induced renal damage globally, strategies for effective prevention or management of kidney damage remain limited ( Cao et al, 2020 ; James et al, 2020 ; Kellum et al, 2021 ).…”

Sirtuins in kidney diseases: potential mechanism and therapeutic targets

“…The main risk factors of kidney disease include age [ 114 ], smoking, obesity [ 115 ], hypertension [ 116 ], diabetes [ 117 ], cardiovascular disease [ 118 ], hyperuricemia [ 119 ], and environmental factors [ 120 ]. Notably, sirtuins modulate most of these risk factors [ 23 ], and slow the progression of renal nephropathy by regulating metabolic homeostasis, autophagy, apoptosis, mitochondrial biogenesis, and oxidative stress; improving serum creatinine and blood urea nitrogen levels and reducing proteinuria [ 121 – 124 ]. Following is an overview of sirtuins in specific renal cells (Figs.…”

Molecular Mechanisms of Oxidative Stress in Acute Kidney Injury: Targeting the Loci by Resveratrol

“…This results from mitochondrial permeability transition pore (mPTP) opening, downregulation of a regulator of the NAD pool (nicotinamide phosphoribosyl transferase), and overactivation of poly (ADP-ribose) polymerases-1, resulting in a lowered activation of SIRT and consequent decreased SIRT1 levels. This decreased deacetylation function of SIRT1 causes its downstream targets to become acetylated, and inactive peroxisome-proliferator-activated receptor gamma coactivator 1-alpha elevates the level of oxidative stress by inhibiting manganese superoxide dismutase (MnSOD), promoting ROS generation, and lowering fatty acid β-oxidation [ 47 ]. Depleted SIRT3 is known to involve mitochondrial integrity, ATP production, and antioxidant defense system and increases oxidative stress, inflammation, and cellular apoptosis [ 46 ].…”