Acute kidney injury (AKI) is not as harmless as previously thought since it may lead to chronic kidney disease (CKD). Because most of the time ischemic AKI occurs unexpectedly, it is difficult to prevent its occurrence and there are no specific therapeutic approaches to prevent the AKI to CKD transition. We aimed to determine whether mineralocorticoid receptor blockade (MRB) in the first days after ischemia/reperfusion (IR) can prevent progression to CKD. Four groups of male Wistar rats were included: sham and three groups of bilateral renal ischemia for 45 min, one without treatment and the other two receiving spironolactone for 5 or 10 days, starting 24 h after IR. The rats were studied at 10 days or 5 months after ischemia induction. After 5 months of follow-up, the untreated group exhibited clear evidence of AKI to CKD progression, such as proteinuria, reduced renal blood flow, tubulointerstitial fibrosis, glomerulosclerosis and glomerular hypertrophy. All these alterations were prevented by both spironolactone treatments initiated 24 h after IR, the 10-day treatment being more effective. Within the early mechanisms of the MRB protective effect are the reduction of inflammation and increased endothelin-B-receptor expression and endothelial nitric oxide synthase activation in the first 10 days after IR. We propose that MRB, administered 24 h after the ischemic injury that leads to AKI, reduces inflammation and promotes efficient tissue repair that avoids the AKI to CKD transition. These data highlight a therapeutic window to preclude CKD development after AKI.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health burdens with rising prevalence. Their bidirectional relationship with cardiovascular dysfunction, manifesting as cardio-renal syndromes (CRS) types 3 and 4, underscores the interconnectedness and interdependence of these vital organ systems. Both the kidney and the heart are critically reliant on mitochondrial function. This organelle is currently recognized as a hub in signaling pathways, with emphasis on the redox regulation mediated by glutathione (GSH). Mitochondrial dysfunction, including impaired bioenergetics, redox, and biogenesis pathways, are central to the progression of AKI to CKD and the development of CRS type 3 and 4. This review delves into the metabolic reprogramming and mitochondrial redox signaling and biogenesis alterations in AKI, CKD, and CRS. We examine the pathophysiological mechanisms involving GSH redox signaling and the AMP-activated protein kinase (AMPK)-sirtuin (SIRT)1/3-peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis in these conditions. Additionally, we explore the therapeutic potential of GSH synthesis inducers in mitigating these mitochondrial dysfunctions, as well as their effects on inflammation and the progression of CKD and CRS types 3 and 4.

Unilateral ureteral obstruction (UUO) is an animal rodent model that allows the study of obstructive nephropathy in an accelerated manner. During UUO, tubular damage is induced, and alterations such as oxidative stress, inflammation, lipid metabolism, and mitochondrial impairment favor fibrosis development, leading to chronic kidney disease progression. Sulforaphane (SFN), an isothiocyanate derived from green cruciferous vegetables, might improve mitochondrial functions and lipid metabolism; however, its role in UUO has been poorly explored. Therefore, we aimed to determine the protective effect of SFN related to mitochondria and lipid metabolism in UUO. Our results showed that in UUO SFN decreased renal damage, attributed to increased mitochondrial biogenesis. We showed that SFN augmented peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and nuclear respiratory factor 1 (NRF1). The increase in biogenesis augmented the mitochondrial mass marker voltage-dependent anion channel (VDAC) and improved mitochondrial structure, as well as complex III (CIII), aconitase 2 (ACO2) and citrate synthase activities in UUO. In addition, lipid metabolism was improved, observed by the downregulation of cluster of differentiation 36 (CD36), sterol regulatory-element binding protein 1 (SREBP1), fatty acid synthase (FASN), and diacylglycerol O-acyltransferase 1 (DGAT1), which reduces triglyceride (TG) accumulation. Finally, restoring the mitochondrial structure reduced excessive fission by decreasing the fission protein dynamin-related protein-1 (DRP1). Autophagy flux was further restored by reducing beclin and sequestosome (p62) and increasing B-cell lymphoma 2 (Bcl2) and the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I). These results reveal that SFN confers protection against UUO-induced kidney injury by targeting mitochondrial biogenesis, which also improves lipid metabolism.

Major cardiovascular events are a common complication in patients with chronic kidney disease (CKD). Endothelial dysfunction can contribute to the cardiovascular injury observed in CKD. Here, we used a rat model of acute kidney injury to CKD transition to investigate heart alterations in the pathway activating endothelial nitric oxide synthase (eNOS) and its impact on the cardiac injury observed during CKD progression. Fifty male Wistar rats were subjected to sham surgery ( n = 25) or bilateral renal ischemia-reperfusion (IR-CKD) for 45 min ( n = 25). Rats were studied on a monthly basis up to 5 mo ( n = 5). In another set of sham and IR-CKD rats, l-arginine was administered starting on the third month after renal ischemia. CKD development and cardiac alterations were monitored in all groups. CKD was characterized by a progressive increase in proteinuria and renal dysfunction that was evident after the fifth month of followup. Heart hypertrophy was observed starting on the fourth month after ischemia-reperfusion. There was a significant increase in brain natriuretic peptide levels. In the heart, IR-CKD rats had increased eNOS phosphorylation at threonine 495 and reduced eNOS-heat shock protein-90α interactions. l-Arginine administration prevented the heart alterations observed during CKD and increased eNOS coupling/dimerization and activation. In summary, CKD progression is accompanied by cardiac hypertrophy, fibrosis, oxidative stress, and increased brain natriuretic peptide levels. These alterations were associated with limited eNOS activation in the heart, which may result in reduced nitric oxide bioavailability and contribute to cardiac injury during CKD.