Clerodendranthus spicatus-Cordyceps cicadae regulates mitophagy and protects renal tubular epithelial cells from hyperuricemic nephropathy

Abstract

Ethnopharmacological relevance: Clerodendranthus spicatus (CS) and Cordyceps cicadae (CC) are both medicine and food. They have long been used to treat kidney disease, but their mechanisms for treating hyperuricemic nephropathy (HN) are not yet clear.

Aim: We investigated the effect and mechanism of Clerodendranthus spicatus-Cordyceps cicadae (CS-CC) in HN treatment.

Methods: We detected the chemical profiling of CS-CC freeze-dried powder, drug-containing serum and drug-containing intracellular fluid by UHPLC-Q Exactive Orbitrap-HRMS. We explored the effective components as well as underlying mechanisms of CS-CC in HN treatment via network pharmacological analysis. We constructed HN rat models induced by gavaging potassium oxonate and uric acid (UA) for three weeks, and performed biochemical and pathological tests as well as histological observation. The expressions of fibrosis-associated proteins were quantitatively analyzed using immunohistochemistry staining and western blot analysis. For in vitro studies, we measured the metabolic fluxes in UA-treated HK-2 cells using Seahorse XFe24 analyzer and flow cytometric analysis. Mitophagy-associated proteins were evaluated using immunofluorescence co-localization analysis and western blot analysis.

Results: A total of 14 simultaneous constituents of CS-CC in vivo and in vitro were identified. Network pharmacological analysis highlighted CS-CC regulated mitophagy in HN. CS-CC treatment effectively enhanced renal function and ameliorate renal fibrosis in HN rats. We found PINK1-mediated mitophagy was suppressed in HN, while CS-CC treatment could restore cellular metabolism, activate mitophagy and protect tubular epithelial cells in HN.

Conclusions: PINK1-mediated mitophagy was significantly inhibited in HN, whereas CS-CC treatment demonstrated remarkable efficacy in attenuating renal fibrosis and promoting mitophagy to protect tubular epithelial cells in HN.

Keywords: Clerodendranthus spicatus; Cordyceps cicadae; Fibrosis; Hyperuricemic nephropathy; Mitophagy; Tubular epithelial cells.