Renoprotective activity of Ribes diacanthum pall (RDP) against inflammation in cisplatin-stimulated mice model and human renal tubular epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Ribes diacanthum Pall (RDP) is mostly distributed in Mongolia. As a Mongolian folk medicinal plant, it is traditionally used to treat kidney diseases by the native inhabitants of Mongolia due to its effect of increasing urine output and eliminating edema. However, its renal protection mechanism remains to be elucidated. AIM OF THE STUDY: To assess the pharmacological mechanism of RDP from an anti-inflammatory point of view using cisplatin (CDDP)-induced kidney injury models in vivo and in vitro. The influence of RDP on the chemotherapy efficacy of CDDP was also evaluated in vitro. MATERIALS AND METHODS: We established a CDDP-induced nephrotoxicity mouse model and a Human Renal Tubular Epithelial (HK-2) damage cellular model, respectively. In vivo, kidney function, the content of urine albumin, and renal histopathology examination were performed to observe the kidney injury. Moreover, the expression and secretion of inflammatory cytokines and adhesive molecules were examined by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and real-time PCR. The key protein levels of mitogen-activated protein kinase/nuclear factor kappa B (MAPK/NF-κB) signaling pathway were measured by western blotting analysis. Electrophoretic mobility shift assay (EMSA) was carried out to detect the activation of NF-κB. In vitro, inflammatory mediators and the proteins related to the NF-κB signaling pathway in HK-2 cells were measured by western blotting analysis. Besides, A549 cell lines were treated with CDDP and RDP to explore RDP's impact on CDDP chemotherapy. RESULTS: Gavage RDP decreased the elevated levels of serum creatinine (Scr), urea nitrogen (BUN), as well as the ratio of urine albumin and creatinine, ameliorated pathological changes of kidney tissue. Correspondingly, the RDP administration group showed a higher survival rate than that of the CDDP exposed group. The expression levels of a plethora of inflammatory mediators were inhibited by RDP treatment compared with the CDDP-exposed group. Furthermore, protein expression levels of MAPK/NF-κB signaling pathway significantly decreased after RDP intervention. For in vitro studies, we confirmed the inhibitory effect of RDP on relative protein expressions involving in the NF-κB pathway. The results also showed that RDP had no impairment on the inhibitory effect of CDDP on A549 cells. CONCLUSION: These findings demonstrated RDP's anti-inflammatory effect against CDDP nephrotoxicity through in vivo and in vitro experiments, and suggested that RDP may have a potential application as an adjuvant medication for CDDP chemotherapy and other inflammatory kidney diseases.

Ribes diacanthum Pall (RDP) ameliorates UUO-induced renal fibrosis via both canonical and non-canonical TGF-ß signaling pathways in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ribes diacanthum Pall (RDP), a folk medicine, has been widely used in Mongolia to treat urinary system diseases. AIM OF THE STUDY: To investigate the effectiveness of RDP on unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis and the underlying mechanisms. MATERIALS AND METHODS: A total of 60 mice were randomly divided into six groups: sham group, sham plus RDP (40 mg/kg) group, UUO model group, and UUO model plus RDP (10, 20 or 40 mg/kg) groups. After surgery, aqueous extract of RDP were administrated intragastrically (i.g) daily for a week and ipsilateral kidneys were collected seven days after surgery. Levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were detected to reflect the kidney injury. Hematoxylin & eosin and Masson's trichrome staining were used to evaluate the kidney morphological changes and fibrosis, respectively. ELISA was used to examine the levels of pro-inflammatory cytokines. Immunohistochemistry, western blot and PCR were used to examine the expression levels of key proteins involved in transforming growth factor (TGF-ß)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. RESULTS: RDP treatment attenuates the level of BUN and kidney fibrosis in UUO mice, decreases the expressions of interleukin-6, tumor necrosis factor-α, Interleukin-1α, TGF-ß1, monocyte chemotactic protein-1, α-smooth muscle actin, collagen I, fibronectin, and vimentin, while increases the expressions of E-cadherin and hepatocyte growth factor. Moreover, RDP administration significantly decreases the levels of p-Smad2/3, p-ERK1/2, p-p38 and p-JNK, while increases the expression level of Smad7 in UUO models. CONCLUSION: These data demonstrate that RDP ameliorates renal fibrosis through TGF-ß/Smad and MAPK pathways in a UUO mouse model.

The protective effects of Ribes diacanthum Pall on cisplatin-induced nephrotoxicity in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ribes diacanthum Pall. (Saxifragaceae), a Mongolian folk medicinal plant, was used to treat urinary system diseases. The present work aims to investigate the protective effects of Ribes diacanthum Pall (RDP) against cisplatin-induced nephrotoxicity. METHODS: The renal injury was modeled by intraperitoneal injection of cisplatin for 5 consecutive days (5 mg/kg). Nephroprotection of RDP was investigated by oral administration of RDP aqueous extract at a daily dose of 40 mg/kg for 14 consecutive days, starting 7 days prior to cisplatin administration. RESULTS: We demonstrated that pretreatment with RDP aqueous extract protected the mice from death induced by cisplatin administration. RDP treatment also significantly reduced blood urea nitrogen (BUN) and serum creatinine (Cr) levels observed in cisplatin-administrated mice. Histopathological analysis demonstrated that RDP administration protected cisplatin-induced renal tubular cell apoptosis. Further western blotting analysis revealed that RDP significantly reversed cisplatin-increased expression levels of cleaved-Caspase-3, Bax and cisplatin-decreased expression level of Bcl-2 in renal tissue. Finally, RDP markedly enhanced enzyme activities of reduced superoxide dismutase (SOD), Heme oxygenase 1 (HO-1) and catalase (CAT), suppressed lipid peroxidation as well as reactive oxygen species (ROS) production. CONCLUSION: We concluded that RDP displayed nephroprotective effects against cisplatin-induced renal tubular cell apoptosis, possibly associated with both enhanced antioxidase activity and suppressed ROS generation. Given the major nephrotoxicity of cisplatin cancer chemotherapy, RDP might be a potential candidate for neoadjuvant chemotherapy.