UCP2-induced hypoxia promotes lipid accumulation and tubulointerstitial fibrosis during ischemic kidney injury

Abstract

Mitochondrial dysfunction leads to loss of renal function and structure; however, the precise mechanisms by which mitochondrial function can regulate renal fibrosis remain unclear. Proximal tubular cells (PTCs) prefer fatty acid oxidation as their energy source and dysregulation of lipid metabolism has been linked to tubulointerstitial fibrosis (TIF). Here, we demonstrated that mitochondrial uncoupling protein 2 (UCP2) regulates TIF through the stimulation of lipid deposition and extracellular matrix (ECM) accumulation. We show that UCP2 expression was increased in human biopsy sample and mouse kidney tissues with TIF. Moreover, UCP2-deficient mice displayed mitigated renal fibrosis in I/R-induced mouse model of TIF. Consistent with these results, UCP2 deficiency displayed reduced lipid deposition and ECM accumulation in vivo and in vitro. In UCP2-deficient PTCs, inhibition of TIF resulted from downregulation of hypoxia-inducible factor-1α (HIF-1α), a key regulator of lipid metabolism and ECM accumulation. Furthermore, we describe a molecular mechanism by which UCP2 regulates HIF-1α stabilization through regulation of mitochondrial respiration and tissue hypoxia during TIF. HIF-1α inhibition by siRNA suppressed lipid and ECM accumulation by restoration of PPARα and CPT1α, as well as suppression of fibronectin and collagen I expression in PTCs. In conclusion, our results suggest that UCP2 regulates TIF by inducing the HIF-1α stabilization pathway in tubular cells. These results identify UCP2 as a potential therapeutic target in treating chronic renal fibrosis.

Transcriptome analysis reveals brown adipogenic reprogramming in chemical compound-induced brown adipocytes converted from human dermal fibroblasts

“…Ucp1 is highly abundant in brown and beige adipocytes in vivo, while Ucp2 is ubiquitously expressed across various tissues and cell types 27 , 28 . Gene targeting and RNA interference approaches have indicated that UCP2 has a weak uncoupling activity, but UCP2 is physiologically required for different functions such as regulation of mitochondrial oxidative stress and energy metabolism 29 , 30 .…”

The Vicious Cycle of Renal Lipotoxicity and Mitochondrial Dysfunction

“…Ke et al reported that UCP2 expression is increased in human biopsy samples and mice kidney tissues with tubulointerstitial fibrosis but UCP2 deficient mice display reduced lipid accumulation and attenuated hypoxia in kidney tissue. Compared with wildtype mice, the expression of PPARα and CPT1α, which are the major regulators of lipid metabolism, is restored in UCP2 deficient mice (Ke et al, 2020). Both CPT1 and ACO2 are the rate-limiting enzymes of FA β-oxidation.…”

CPT1α maintains phenotype of tubules via mitochondrial respiration during kidney injury and repair

“…Primary PTECs were cultured from collagenase-digested cortical fragments of mice (about 21 days) kidneys according to a modified method previously described [ 20 , 21 ]. In brief, after been dissected and collagenase digested, two nylon sieves with the pore sizes of 250 and 80 μm were used to yield proximal tubule fragments, which were then washed, resuspended, and seeded onto collagen-coated permeable PTFE-filter supports and cultured for 48 h in a standard humidified incubator with the medium replaced every 2 days till the organization of a confluent monolayer of cells.…”

“…OCT-embedded kidney tissues were sectioned at 12 μm for oil red O (Sigma-Aldrich, US) and 3 μm for bodipy (D3922, Thermo Fisher, US) staining as previously described [ 6 , 21 , 25 ]. Nuclei were viewed by alum haematoxylin staining.…”