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Some evidence has demonstrated that both inflammation and immune cell dysregulation are coincident at late phase (post 24 h) of sepsis. The present study was designed to determine the pathological role of hyperinflammation and renal immune cells mobilization during late phase of sepsis induced acute kidney injury (S-AKI) and tests the pharmacological effects of PDE-4 inhibitor on these events. Sepsis was induced by cecal ligation puncture and renal function, oxidative-inflammatory stress biomarkers were assessed after 24 h. PDE-4 inhibitor was administered for 7 days prior to induction of S-AKI. Renal immune cells infiltration during sepsis was analyzed by H&E staining and papanicolaou staining method was used for detecting leukocytes and cast in urinary sediments, periodic acid schiff (PAS) staining was used for detection of brush border loss. AKI developed 24 h post sepsis insult as depicted by increase in serum creatinine, blood urea nitrogen (BUN), renal oxidative stress, and elevated inflammatory biomarkers levels. Moreover, septic rats displayed increased bacterial load, renal expression of phosphodiesterase-4B, 4D isoforms, enhanced vascular permeability, caspase-3 and myeloperoxidase activity, electrolyte imbalance, reduced Na + K + ATPase activity, declined cAMP levels, increased interstitial leukocyte infiltration, and leakage in urinary sediments along with histological alterations. Pre-treatment with roflumilast at high dose completely prevented the various AKI associated manifestations in septic rats. Renal hyper-inflammation and leukocyte infiltration was detected in late phase of S-AKI. Roflumilast pre-treatment resolved sepsis induced renal dysfunction and histological damage by suppressing late phase renal immune cells invasion and anti-inflammatory effects mediated by upregulation of renal cAMP levels.

Aberrant activation of Wnt/β-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/β-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p) and renal cisplatin accumulation and uptake in cortical slices were determined after the 5th day by atomic absorption spectroscopy. Levels of pro-inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the β-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage, and fibrosis. Notably, Wnt/β-catenin inhibitor pyrvinium (60 µg/kg; p.o) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/β-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression.