Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg−1·d−1, i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
See EJ, Jayasinghe K, Glassford N, Bailey M, Johnson DW, Polkinghorne KR, et al. Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure. Kidney Int. 2019;95:160–72.
Chawla LS, Amdur RL, Amodeo S, Kimmel PL, Palant CE. The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int. 2011;79:1361–9.
Hoste EAJ, Kellum JA, Selby NM, Zarbock A, Palevsky PM, Bagshaw SM, et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018;14:607–25.
Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 2015;11:264–76.
Ullah MM, Basile DP. Role of renal hypoxia in the progression from acute kidney injury to chronic kidney disease. Semin Nephrol. 2019;39:567–80.
Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010;16:535–43. 1p following 143
Xiao L, Zhou D, Tan RJ, Fu HH, Zhou LL, Hou FF, et al. Sustained activation of Wnt/β-catenin signaling drives AKI to CKD progression. J Am Soc Nephrol. 2016;27:1727–40.
Tanaka S, Tanaka T, Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Ren Physiol. 2014;307:F1187–95.
Chevalier RL. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction. Am J Physiol Ren Physiol. 2016;311:F145–61.
Takaori K, Nakamura J, Yamamoto S, Nakata H, Sato Y, Takase M, et al. Severity and frequency of proximal tubule injury determines renal prognosis. J Am Soc Nephrol. 2016;27:2393–406.
Liu BC, Tang TT, Lv LL, Lan HY. Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int. 2018;93:568–79.
Schödel J, Ratcliffe PJ. Mechanisms of hypoxia signalling: new implications for nephrology. Nat Rev Nephrol. 2019;15:641–59.
Hill P, Shukla D, Tran MG, Aragones J, Cook HT, Carmeliet P, et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J Am Soc Nephrol. 2008;19:39–46.
Bernhardt WM, Câmpean V, Kany S, Jürgensen JS, Weidemann A, Warnecke C, et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol. 2006;17:1970–8.
Kimura K, Iwano M, Higgins DF, Yamaguchi Y, Nakatani K, Harada K, et al. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Ren Physiol. 2008;295:F1023–9.
Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007;17:3810–20.
Li ZL, Lv LL, Tang TT, Wang B, Feng Y, Zhou LT, et al. HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation. Kidney Int. 2019;95:388–404.
Tang TT, Wang B, Wu M, Li ZL, Feng Y, Cao JY, et al. Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI. Sci Adv. 2020;6:eaaz0748.
Luo CW, Zhou S, Zhou ZM, Liu YH, Yang L, Liu JF, et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. J Am Soc Nephrol. 2018;29:1238–56.
Li Z, You Q, Zhang X. Small-molecule modulators of the hypoxia-inducible factor pathway: development and therapeutic applications. J Med Chem. 2019;62:5725–49.
McDonough MA, McNeill LA, Tilliet M, Magalang UJ, Scherer PE. Selective inhibition of factor inhibiting hypoxia-inducible factor. J Am Chem Soc. 2005;127:7680–1.
Li L, Kang H, Zhang Q, D’Agati VD, Al-Awqati Q, Lin FM. FoxO3 activation in hypoxic tubules prevents chronic kidney disease. J Clin Invest. 2019;129:2374–89.
Baumann B, Hayashida T, Liang X, Schnaper HW. Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3. Kidney Int. 2016;90:797–808.
Tang TT, Lv LL, Wang B, Cao JY, Feng Y, Li ZL, et al. Employing macrophage-derived microvesicle for kidney-targeted delivery of dexamethasone: an efficient therapeutic strategy against renal inflammation and fibrosis. Theranostics. 2019;9:4740–55.
Liu D, Wen Y, Tang TT, Lv LL, Tang RN, Liu H, et al. Megalin/Cubulin-lysosome-mediated albumin reabsorption is involved in the tubular cell activation of NLRP3 inflammasome and tubulointerstitial inflammation. J Biol Chem. 2015;290:18018–28.
Chan MC, Ilott NE, Schödel J, Sims D, Tumber A, Lippl K, et al. Tuning the transcriptional response to hypoxia by inhibiting hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases. J Biol Chem. 2016;291:20661–73.
Li ZL, Lv LL, Wang B, Tang TT, Feng Y, Cao JY, et al. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway. FASEB J. 2019;33:12630–43.
Koivunen P, Hirsilä M, Günzler V, Kivirikko KI, Myllyharju J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem. 2004;279:9899–904.
Sawhney S, Marks A, Fluck N, Levin A, McLernon D, Prescott G, et al. Post-discharge kidney function is associated with subsequent ten-year renal progression risk among survivors of acute kidney injury. Kidney Int. 2017;92:440–52.
Shu SQ, Wang Y, Zheng ML, Liu Z, Cai J, Tang C, et al. Hypoxia and hypoxia-inducible factors in kidney injury and repair. Cells. 2019;8:207.
Bracken CP, Fedele AO, Linke S, Balrak W, Lisy K, Whitelaw ML, et al. Cell-specific regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment. J Biol Chem. 2006;281:22575–85.
Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. 2006;66:3688–98.
Chen WC, Lin HH, Tang MJ. Matrix-stiffness-regulated inverse expression of Krüppel-like factor 5 and Krüppel-like factor 4 in the pathogenesis of renal fibrosis. Am J Pathol. 2015;185:2468–81.
Shindo T, Manabe I, Fukushima Y, Tobe K, Aizawa K, Miyamoto S, et al. Krüppel-like Zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med. 2002;8:856–63.
Kushida N, Nomura S, Mimura I, Fujita T, Yamamoto S, Nangaku M, et al. Hypoxia-inducible factor-1α activates the transforming growth factor-β/SMAD3 pathway in kidney tubular epithelial cells. Am J Nephrol. 2016;44:276–85.
Nayak BK, Shanmugasundaram K, Friedrichs WE, Cavaglierii RC, Patel M, Barnes J, Block K. HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. Diabetes. 2016;65:1387–97.
Wilkins SE, Abboud MI, Hancock RL, Schofield CJ. Targeting protein-protein interactions in the HIF system. ChemMedChem 2016;11:773–86.
Tal R, Shaish A, Bangio L, Peled M, Breitbart E, Harats D. Activation of C-transactivation domain is essential for optimal HIF-1 alpha-mediated transcriptional and angiogenic effects. Microvasc Res. 2008;76:1–6.
Yeh TL, Leissing TM, Abboud MI, Thinnes CC, Atasoylu O, Holt-Martyn JP, et al. Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials. Chem Sci. 2017;8:7651–68.
Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12:157–68.
The authors thank Chen-chen Zhang (Southeast University School of Medicine) for confocal image acquisition and valuable technical support. This study was supported by the National Natural Science Foundation of China (82000648, 8203000544, 81720108007, and 81470922), the National Key Research and Development Program of China (2018YFC1314002), the Natural Science Foundation of Jiangsu Province (BK20200363), the Innovative and Entrepreneurial Talent (Doctor) of Jiangsu Province and the Special Fund for Basic Scientific Research of Central Universities (2242020K40151).
The authors declare no competing interests.
About this article
Cite this article
Li, Zl., Wang, B., Lv, Ll. et al. FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00617-4
- acute kidney injury
- chronic kidney disease
- renal fibrosis
- HIF-1α C-terminal activation domain