Abstract
This study evaluated if there is a sexual dimorphism in the acute kidney injury (AKI) to chronic kidney disease (CKD) transition and the time-course of the potential mechanisms involved in the dimorphic response. Female and male rats were divided into sham-operated or underwent 45-min renal ischemia (F + IR, and M + IR). All groups were studied at 24-h and 1, 2, 3, or 4-months post-ischemia. Additionally, oophorectomized rats were divided into sham or IR groups. After 24-h, AKI extent was simllar in females and males, but female rats exhibited less oxidative stress and increased renal GSH content. After 4-months and despite similar AKI, the M + IR group developed CKD characterized by proteinuria, tubulointerstitial fibrosis, glomerular hypertrophy, increased oxidative stress and a reduction in HIF1α and VEGF from the 1st-month and persisting throughout the time-course studied. Interestingly, the F + IR group did not develop CKD due to lesser oxidative stress and increased eNOS, TGFβ and HIF1α mRNA levels from the 1st-month after IR. Whereas, oophorectomized rats did develop CKD. We found a sexual dimorphic response in the AKI to CKD transition. Early antioxidant defense and higher TGFβ, HIF1α and eNOS were among the renoprotective mechanisms that the F + IR group demonstrated.
Highlights
The tubular epithelium can recover from lethal or sublethal cell damage, cellular processes in endothelial and tubular cells may not fully recover, thereby conditioning the development of progressive renal dysfunction[11]
We show that after 24-h that of inducing renal injury by 45 min of renal bilateral ischemia, female and male rats exhibited a similar extent of IRI, but after 4 months of the initial IRI, the M + IR group, but not the F + IR group, exhibited clear signs of chronic kidney disease (CKD), characterized by proteinuria, increased oxidative stress and structural changes such as: glomerular hypertrophy and tubulointerstitial fibrosis
These findings provide evidence to support that the F + IR group were protected from the development of CKD, even though they had a similar degree of initial acute kidney injury (AKI) (Fig. 1)
Summary
The tubular epithelium can recover from lethal or sublethal cell damage, cellular processes in endothelial and tubular cells may not fully recover, thereby conditioning the development of progressive renal dysfunction[11]. Several theories have tried to explain how an episode of AKI leads to renal function and structure injury over time These theories include repeated cycles of damage and repair[18], rarefaction of peritubular capillaries with the subsequent development of chronic hypoxia[7,19,20], and activation of signaling pathways such as hypoxia inducible www.nature.com/scientificreports/. There is a growing evidence that the pathogenesis, clinical features and prognosis of cardiovascular and renal diseases is completely different between men and women, which makes sense since the physiology of women is different from men In this sense, one of the largest meta-analysis to assess gender differences in the progression of renal diseases included 11,000 patients referred from 60 different studies and showed that women demonstrate lower progression compared to men in different renal diseases, such as polycystic kidney disease, IgA nephropathy, membranous glomerulonephritis and CKD27. We evaluated whether there is a sexual dimorphism in the AKI to CKD transition, the time-course of functional and structural alterations in both genders, the effect of oophorectomy on this transition, and the mechanisms responsible for gender differences
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