Nephrotoxicity Induced by Cisplatin Intake in Experimental Rats and Therapeutic Approach of Using Mesenchymal Stem Cells and Spironolactone

Abstract

Chronic kidney disease may lead to subsequent tissue fibrosis. However, many factors can combat injurious stimuli in these tissues aiming to repair, heal, and alleviate any disturbance. Chemokines release, migration of inflammatory cells to the affected site, and activation of fibroblasts for the production of extracellular matrix are commonly observed in this disease. In the last years, many studies have focused on spironolactone (SPL), a mineralocorticoid receptor antagonist, and its pharmacological effects. In the present study, SPL was selected as an anti-inflammatory agent to combat nephrotoxicity and renal fibrosis induced by cisplatin. Mesenchymal stem cells (MSCs) were also selected in addition as a referring agent. Renal fibrosis induced by cisplatin intake significantly increased creatinine, urea, nuclear factor kappa B, insulin-like growth factor-1, fibroblast growth factor-23, and kidney malondialdehyde (MDA) content. Hepatocyte growth factor and renal content of reduced glutathione demonstrated a significant decrease. Histopathological examination of kidney tissues demonstrated marked cellular changes which are correlated with the biochemical results. Oral SPL intake (20 mg/kg/body weight) daily for 4 weeks and MSCs administration (3 × 10 cell/rat) intravenous to the experimental rats resulted in a significant improvement of both the biomarkers studied and the histopathological profile of the renal tissue. Individual administration of spironolactone and MSCs exhibited a marked anti-inflammatory potential and alleviated to a great extent the nephrotoxicity and renal fibrotic pattern induced by cisplatin.

Inflammation and renal fibrosis: Recent developments on key signaling molecules as potential therapeutic targets

“…This combined treatment of telmisartan and vitamin D for CKD-related renal fibrosis awaits clinical trial. Finally, accumulating evidence shows that mesenchymal stem cells (MSCs) have renoprotective actions and reduce renal fibrosis in preclinical models of both AKI and CKD (Elseweidy et al, 2017; Roushandeh et al, 2017; Yokote et al, 2017; Zhu et al, 2017). Likely, their effectiveness is due to the release of multiple factors.…”

Role of mineralocorticoid receptor antagonists in kidney diseases

“…Cisplatin treatment worsens kidney function in patients and increases aldosterone and angiotensin II levels in mice (Okui et al, 2012). In rats, cisplatin treatment increased serum creatinine, serum urea, renal oxidative stress, renal inflammation, and renal fibrosis (Elseweidy et al, 2018). Spironolactone treatment reduced oxidative stress, serum urea, and serum creatinine in cisplatin‐treated rats.…”

“…Spironolactone treatment reduced oxidative stress, serum urea, and serum creatinine in cisplatin-treated rats. It also reduced NF-κB, insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF)-23, and hepatocyte growth factor levels in blood and TNF-α and TGF-ß expression in the kidney (Elseweidy et al, 2018). Spironolactone acts by inhibiting SIRT2 mediated nucleotide excision repair activity in cisplatin-induced peripheral neuropathy (Zhang et al, 2020).…”

Sirt5 Attenuates Cisplatin-Induced Acute Kidney Injury through Regulation of Nrf2/HO-1 and Bcl-2

“…Cisplatin is one of most commonly used chemotherapeutic drugs in the treatment of solid tumors including liver [1], lung [2], breast [3], cervical [4], ovarian [5], and testis [6] cancers. Although cisplatin has been shown to be one of the most effective anticancer drugs, its use in clinical application is limited because of its side effects in normal tissues [7–9]. The major consequences during cisplatin treatment are nephrotoxicity, ototoxicity, and neurotoxicity.…”