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HIF‐1alpha and AMPK interactions regulate cellular hypoxia adaptation in the subtotal nephrectomy model of CKD
Author(s) -
Singh Prabhleen,
Satriano Joseph,
Li Hui,
Hallows Kenneth
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.910.10
Subject(s) - ampk , autophagy , chemistry , hypoxia (environmental) , apoptosis , kidney , medicine , hypoxia inducible factors , gene knockdown , endocrinology , cancer research , microbiology and biotechnology , protein kinase a , biology , kinase , biochemistry , organic chemistry , oxygen , gene
HIF‐1α activation in subtotal nephrectomy (STN) ameliorates hypoxia and improves GFR. The AMPK pathway facilitates adaptation to hypoxia, and there is significant overlap between the actions and targets of HIF‐1α and AMPK. Here we investigate the effects of HIF‐1α activation on cellular physiology and the interaction between HIF‐1α and AMPK in early STN kidney. Kidneys harvested from control, 1‐week STN, and STN treated with DMOG (HIF‐1α inducer) were examined by Western blotting. The expression of molecular markers for hypertophy (p70S6k) and apoptosis (cleaved caspase‐3) were elevated in STN, while a marker for autophagy (LC3II/LC3I) was reduced. HIF‐1α induction completely reversed these processes. The activated AMPK (pAMPK) to total AMPK ratio was low in STN and increased by HIF‐1α activation. All results were significant at p<0.05. Interactions between HIF‐1α and AMPK in HK2 and MDCK with AMPK knockdown (KD) cell lines were investigated. Consistent with the in vivo data, DMOG treatment increased pAMPK levels, increased LC3II/LC3I and lowered p70S6k in HK2 cells. These effects were reversed by HIF‐1α inhibition by YC‐1, with a dramatic increase in cleaved caspase3. AMPK activation by AICAR blocked the increase in cleaved caspase3 induced by YC‐1, and this was reversed in the AMPK KD cells. Inhibition of LC3II/LC3I by YC‐1 was AMPK‐independent. Finally, both AMPK and HIF‐1α activation inhibited p70S6K. We propose that HIF‐1α activation in the STN kidney facilitates hypoxic adaptation and cell survival by inhibiting hypertrophy and apoptosis and activating autophagy and the AMPK pathway. These novel findings suggest that HIF‐1α and AMPK closely interact with each other to mount a coordinated cellular response to hypoxic stress.