Ageing reduces angiotensin II type 1 receptor antagonism mediated pre-conditioning effects in ischemic kidneys by inducing oxidative and inflammatory stress.

BACKGROUND: Ischemia/reperfusion (I/R) injury is a common cause of acute kidney injury (AKI), which occurs clinically during renal organ transplantation and major cardiac surgeries. Previously, it was demonstrated that angiotensin II type 1 receptor (AT1) receptor antagonism is beneficial in the resolution of AKI episodes in young rats by reducing inflammation and oxidative stress. However, studies have shown that aged kidneys are refractory to surgical ischemic pre-conditioning due to increased oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. Therefore, the present study was designed to evaluate the effects of pharmacologically induced pre-conditioning on I/R induced AKI in aged kidneys. METHODS: AKI was induced by clamping both renal pedicels for 45 min followed by 24 h of reperfusion. The AT1 receptor antagonist, losartan was administered for three days prior to I/R injury induction in both aged and young rats. Renal outcomes were assessed by serum creatinine, creatinine clearance and proteinuria, renal antioxidant enzyme assays, membrane Na+K+ATPase activity, inflammatory biomarkers, and histological studies. RESULTS: AKI developed 24 h post ischemia, as indicated by elevated serum creatinine levels, proteinuria, oxidative stress, reduced membrane Na+K+ATPase activity, increased inflammatory biomarkers levels and histological damage including cellular infiltration, tubular thickening, tubular dilation and necrosis. Losartan pre-treatment significantly improved renal dysfunction and histological alterations in young rats subjected to I/R injury. However, this treatment did not prevent various AKI manifestations in aged rats due to elevated oxidative and inflammatory stress mediated via tubular dysfunction and damage. CONCLUSION: We conclude that AT1 receptor antagonism is not beneficial against renal I/R induced AKI in aged rats.

Factors affecting the transition of acute kidney injury to chronic kidney disease: Potential mechanisms and future perspectives.

Acute kidney injury (AKI) is defined as a rapid loss of kidney function characterised by inflammation and cell death, ultimately leading to further functional and structural renal alterations. Based on experimental and epidemiological pieces of evidence, AKI may progress to chronic kidney disease (CKD) even after a recovery period due to maladaptive repair and other underlying mechanisms such as heightened Wnt signalling, overstimulation of the renin-angiotensin-aldosterone-system (RAAS) pathway, epigenetic alterations and inhibition of hypoxia-inducible factor (HIF) dependent defences. It has been reported that RAAS activation subsequent to renal insult mediates inflammatory and fibrotic mechanisms, which are a hallmark of CKD. Moreover, interesting evidence regarding the exposure-dependent dual role of Wnt signalling in both injury and repair, epigenetic changes underlying kidney disease suggest a potential therapeutic role of these pathways in AKI to CKD continuum. In addition, the hypoxia-independent renal benefits of erythropoietin such as anti-apoptosis and tubular regeneration also present an auspicious target which could be useful in clinical settings. In this review, the specific roles of these pathways in kidney disease, their pathological mechanisms and therapeutic strategies are discussed. Moreover, notable reports concerning stem cell therapy which hold promise in halting AKI-CKD continuum will be elaborated.