Both endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-β1-treated HK-2 cells. Interestingly, in both TM- or TGF-β1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.

Glomerular podocytes are characterized by terminally differentiated epithelial cells with limited proliferating ability; thus, podocyte loss could not be fully compensated by podocyte regeneration. A large body of clinical studies collectively demonstrated that podocyte loss correlated with glomerular diseases progression. Both podocyte death and podocyte detachment lead to podocyte loss; however, which one is the main cause remains controversial. Up to date, multiple mechanisms are involved in podocyte death, including programmed apoptotic cell death (apoptosis and anoikis), programmed nonapoptotic cell death (autophagy, entosis, and podoptosis), immune-related cell death (pyroptosis), and other types of cell death (necroptosis and mitotic catastrophe-related cell death). Apoptosis is considered a common mechanism of podocyte loss; however, most of the data were generated in vitro and the evidence of in vivo podocyte apoptosis is limited. The isolation of podocytes in the urine and subsequent culture of urinary podocytes in vitro suggest that detachment of viable podocytes could be another important mechanism for podocyte loss. In this review, we summarize recent advances that address this controversial topic on the specific circumstances of podocyte loss.

RA (Retinoid acid) is synthesized mainly in the liver and has multiple functions in development, cell differentiation and proliferation, and regulation of inflammation. RA has been used to treat multiple diseases such as cancer and skin disorders. The kidney is a major organ for RA metabolism, which is altered in the diseased condition. RA is known to have renal protective effects in multiple animal models of kidney disease. RA has been shown to ameliorate podocyte injury through induction of expression of differentiation markers and regeneration of podocytes from its progenitor cells in animal models of kidney disease. The effects of RA in podocytes are mediated mainly by activation of cAMP/PKA pathway via retinoic acid receptor-α (RARα) and activation of its downstream transcription factor KLF15. Screening of RA signaling molecules in human kidney disease reveals RARRES1 as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by both high doses of RA and TNFα. Mechanistically, RARRES1 is cleaved by MMPs to generate soluble RARRES1 which then induces podocyte apoptosis through interaction with intracellular RIOK1. Therefore, a high dose of RA may induce podocyte toxicity through the upregulation of RARRES1. Based on the current findings, to avoid potential side effects we propose three strategies to develop future therapies of RA for glomerular disease: 1) develop RARα- and KLF15-specific agonists; 2) use the combination of a low dose of RARα agonist with PDE4 inhibitors; and 3) use the combination of RARα agonist with RARRES1 inhibitors.

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Retinoic acid receptor responder protein 1 (RARRES1) has been identified as a novel gene for the regulation of podocyte function, and its expression is increased in glomerular disease and associated with disease progression. Increased expression of RARRES1 in podocytes leads to apoptosis through an autocrine effect. Möller-Hackbarth et al. recently found that RARRES1 expression is increased in the endothelial cells in some diseased kidneys to promote podocyte injury, likely through a paracrine effect.