Druggability of lipid metabolism modulation against renal fibrosis

Abstract

Renal fibrosis contributes to progressive damage to renal structure and function. It is a common pathological process as chronic kidney disease develops into kidney failure, irrespective of diverse etiologies, and eventually leads to death. However, there are no effective drugs for renal fibrosis treatment at present. Lipid aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and fibrosis. Numerous studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal fibrosis. Thus, it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney, by targeting critical regulators of lipid metabolism. In this review, we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence, exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis roles. Then, we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid metabolism. Finally, we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.

Keywords: anti-renal fibrosis; drug targets; fatty acid oxidation; lipid metabolism; noncoding RNA.

Fig. 1. The pathological progress in renal fibrosis.

Epithelial cells damage and inflammation that occur when the kidney is subjected to various harmful stimuli during renal fibrosis. In the inflammation branch, a series of immune cells outside the kidney are recruited into the kidney tissue and they secrete various cytokines, which will eventually promote the myofibroblasts activation, serving as the fibrosis executor enabling considerable extracellular matrix production rapidly. The main sources of myofibroblasts are epithelial cells, endothelial cells, pericytes, and fibrocytes (including those from the kidney itself and bone marrow). In the left branch, epithelial cell injury can trigger EMT and epithelial cell loss especially podocyte, which exacerbate renal fibrosis. Injured epithelial cell can also promote the activation of fibroblasts via secreting numerous fibrosis-related factors. Myofibroblast and its produced ECM are the dominantly executors in renal fibrosis, but the source of fibroblasts is not clarified yet, and the contribution of each cell type is still controversial. Wholly, the above epithelial cells damage and inflammation pathway are overlapping and dynamic, which are both regulated by complex molecular networks. Therefore, renal fibrosis is a particularly complicate process. The right gray part indicates the roles of lipid metabolism in fibrosis, and the contents in dotted ellipse are speculated mechanisms remaining to be verified.

Fig. 2. Brief overview of classical TGF-β pathway in renal fibrosis.

Once released from the small latent complex, TGF-β binds to its receptor and activates the SMAD2/3 complex, which later forms complexes with SMAD4 and translocates into the nucleus to regulate gene regulation as a transcriptional factor. SMAD7 acts as an inhibitor of TGF-β mediated profibrotic role in canonical pathway. Several non-canonical pathways may regulate TGF-β signals to some extent. Other pathways such as Wnt, Notch, Hedgehog contribute into renal fibrosis and have a crosstalk with TGF-β signaling, portending the intricacy and intangibility of fibrogenesis mechanically.

Fig. 3. Critical lipid metabolism regulators with potential druggability in the kidney fibrosis discussed in the current review.

Here we use fatty acid (FA) as a schematic example. FA is transported into cells by CD36 primarily or other proteins such as FABP and FATP, then FA can be disposed into the following three directions, lipid droplet, peroxisome, and mitochondria, among which, mitochondrial β-oxidation is a fundamental process for FA metabolism, thus CPT1/2 downregulation or mitochondrial dysfunction will lead to FA deposition. PPARs and their co-activator PGC-1α promote lipid metabolism transcriptionally. While SREBP can enhance lipogenesis through its transcriptionally active N-terminal fragments cleaved in Golgi apparatus. Noncoding RNAs including miR21, miR-9-5p, and TUG1 can control renal fibrosis via lipid metabolism. Targeting these above regulators by utilizing nucleic, antibody, small molecule or phytochemical drug can yield anti-fibrosis effects in the kidney.

Fig. 4. MiRNA/lncRNA performs as upstream mediators to influence renal fibrosis in an epigenetic way.

By improvement of advanced delivery technique, specific target therapy for fibrosis within the kidney tissue can be achieved. Popular loading systems (including viral vector, polymeric vector, liposome, exosome, etc.) are employed to deliver exact miRNA, lncRNA, according siRNA or ASO to the kidney.