Mechanistic Insights into Aldose Reductase-Dependent Modulation of Hypoxia-Inducible Factor-1α in Promoting Renal Fibrosis.

Renal fibrosis (RF) represents the common pathological endpoint of all chronic kidney diseases. According to recent evidence, impaired mitophagy, which facilitates epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells (RTECs), substantially contributes to RF progression, although the underlying mechanisms remain unclear. We previously demonstrated that mitophagy mediated by aldose reductase (AR) promotes EMT of hepatocytes. Further investigations are warranted to elucidate whether AR affects RF and EMT in RTECs through the regulation of impaired mitophagy. In the in vivo study, AR knockout remarkably reduced Phosphoinositide 3-kinase (PI3K) and serine/threonine kinase (AKT) phosphorylation and attenuated hypoxia-inducible factor-1α (HIF-1α) expression, while increasing Pink1 and Parkin expression in unilateral ureteral obstruction (UUO)-exposed renal tissues. These changes were linked with a higher expression ratio of microtubule-associated protein 1 light chain 3 (LC3) II/I; low p62 expression; decreased Snail, α-smooth muscle actin‌ (α-SMA), and vimentin expression; enhanced E-cadherin expression; and a reduction in mitochondrial damage, which collectively contributed to mitigate RF. In the in vitro study, knockdown of AR through siRNA or pharmacological inhibition markedly reduced transforming growth factor-beta 1 (TGF-β1)-induced HIF-1α expression, inhibited PI3K/AKT pathway activation, restored mitochondrial autophagy function, decreased levels of reactive oxygen species (ROS) and mitochondrial permeability transition pore (MPTP) opening, and increased mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP) production, thereby reversing EMT in RTECs. Conversely, AR overexpression exacerbated TGF-β1-induced HIF-1α expression, enhanced PI3K/AKT pathway activation, lowered efficiency of mitophagy, increased MPTP opening and ROS levels, reduced ΔΨm and ATP production, and promoted EMT. These findings highlight AR's role as a facilitator of EMT in RTECs and emphasize its critical contribution to RF progression. This process may be mediated by AR-induced expression of HIF-1α, which stimulates the PI3K/AKT signaling pathway, leading to inhibition of Pink1 and Parkin expression, ultimately decreasing mitophagy occurrence in RTECs.