Short-Term Diet Restriction but Not Alternate Day Fasting Prevents Cisplatin-Induced Nephrotoxicity in Mice

Abstract

Cisplatin (CP) is one of the most preferred platinum-containing antineoplastic drugs. However, even in nontoxic plasma concentrations, it may cause kidney injury. To be able to increase its effective pharmacological dose, its side effects need to be regarded. Diet restriction (DR) has been demonstrated to improve cellular survival in a number of disorders. In this context, we investigated the role of DR in CP-induced nephrotoxicity (CPN). Besides alternate DR, animals were exposed to DR for 3 days prior or after CP treatment. Here, we observed that both 3 days of DR reverses the nephrotoxic effect of CP, which was associated with improved physiological outcomes, such as serum creatine, blood-urea nitrogen and urea. These treatments significantly increased phosphorylation of survival kinases PI3K/Akt and ERK-1/2 and decreased the level of stress kinase JNK were noted. In addition, the activation level of signal transduction mediator p38 MAPK phosphorylation was higher particularly in both three-day DR groups. Next, animals were fed with carbohydrate-, protein- or fat-enriched diets in the presence of CP. Results indicated that not only fasting but also dietary content itself may play a determinant role in the severity of CPN. Our data suggest that DR is a promising approach to reduce CPN by regulating metabolism and cell signaling pathways.

Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging

“…A significant reduction in cisplatin-induced nephrotoxicity was observed in mice that were fasted for 3 days before cisplatin treatment. Histological parameters including tubule damage, glomerular deterioration, brush border degradation, and serum measurements including creatinine and urea levels all indicated less severe kidney damage in fasted mice compared to AL-fed mice ( Gunebakan et al 2020 ). Together, these findings indicate that NP can induce protection in healthy tissue against multiple types of DNA-damaging chemotherapeutics.…”

Beneficial effects of time and energy restriction diets on the development of experimental acute kidney injury in Rat: Bax/Bcl-2 and histopathological evaluation

“…In another study, Eddy et al reported that HF ​​caused inflammation and eventually interstitial fibrosis of kidney tissue [ 85 ]. Also, vacuolization of tubular cells [ 48 ], dilatation of tubules, further damage to glomeruli and proximal tubules [ 74 , 86 ], severe inflammation, destruction of the basement membrane of epithelial cells of renal tubules, and loss of tubular epithelium [ 87 ] resulting from an HF diet have been reported in other histopathological studies.…”

Dietary Restriction for Kidney Protection: Decline in Nephroprotective Mechanisms During Aging

“…Thus, DR ameliorated acute cisplatin- and cadmium nephrotoxicity ( Shaikh et al, 1999 ; Estrela et al, 2017 ). DR with different protein and fat content for 3 days before or after cisplatin-induced AKI reversed the nephrotoxic effect of cisplatin treatment and was associated with phosphorylation of survival kinases PI3K/Akt and ERK-1/2, decreased level of stress kinase JNK, and improved physiological outcomes ( Gunebakan et al, 2020 ). The protective properties of DR against cisplatin-induced AKI were also confirmed using multi-layered omics data (transcriptome, proteome, and N-degradome) correlated with functional parameters ( Späth et al, 2019 ).…”