The use of functional chemical-protein associations to identify multi-pathway renoprotectants.
Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1), which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10-5). At the same concentration (10 µM), both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.
Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Nephrology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Jia
J
Xu
Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Kexin
K
Meng
Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Rui
R
Zhang
Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
He
H
Yang
Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Chang
C
Liao
Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Wenliang
W
Zhu
Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China; Institute of Nephrology, Harbin Medical University, Harbin, China.
Jundong
J
Jiao
D001343:Autophagy; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide; D007674:Kidney Diseases / Q000188:drug therapy; D008869:Microtubule-Associated Proteins / Q000378:metabolism / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*
C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D020011:Protective Agents; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006427:Hemin; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D003474:Curcumin