We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

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We previously reported the expression of scaffolding protein, postsynaptic density‐95 (PSD95) in rat cerebral vascular smooth muscle cells (cVSMC). PSD95 binds with KV1 channels at the plasma membrane of cVSMC to mediate vasodilation. A membrane‐permeable peptide (KV1‐C) that competes for PSD95 binding causes vasoconstriction and blunts vasodilation induced by isoproterenol (ISO). This study explores whether angiotensin II‐induced hypertension (AHT) alters ISO‐induced vasodilation and KV1‐C peptide response. Sprague‐Dawley rats were infused by osmotic pumps with saline or angiotensin II (500ng/kg/min) for 14 days. Blood pressure was measured by tail‐cuff plethysmography. Cerebral arteries (CA) were isolated for pressure myography and protein lysate. Western blot analysis revealed KV1.2 subunits were downregulated by ~70% (n=5) in CA lysates from AHT rats compared to saline rats. In pressurized CA, maximal vasodilation to ISO was reduced by half in AHT rats compared to saline rats. KV1‐C peptide treatment had little effect on CA from AHT rats but it blunted ISO response in CA from saline rats to the level of AHT rats (n=5–8). These findings suggest that a loss of KV1 channel expression and function in CA from AHT rats may account for the blunted ISO response and that KV1‐C peptide confers similar disruption of PSD95‐mediated KV1 channel function in CA from saline rats.