Research progress of augmenter of liver regeneration in acute kidney injury_West China Medical Journal

Authors：

YU Dan ,  PU Tao

Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563099, P. R. China;

Corresponding author：

PU Tao, Email: hf1399@sina.com

Keywords：

Augmenter of liver regeneration; Acute kidney injury; Ischemia/reperfusion injury; Inflammatory; Mitochondria

DOI：

10.7507/1002-0179.202011222

Video：

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Abstract Full text Figures/Tables Video References Cited by

Augmenter of liver regeneration (ALR) is a newly discovered cytokine that can promote liver regeneration and proliferation of damaged liver cells. In the renal tissue, ALR is mainly expressed in the cytoplasm of the medullary loops, collecting ducts and distal convoluted tubules in the renal medulla, and is low in the glomerular and cortical tubules. Various stimulation, such as ischemiacal, hypoxia, poisoning and inflammatory stimulation, can induce the expression of ALR in the epithelial cells of proximal tubule regeneration and the damaged areas of cortex, and participate in the repair process. Current studies have found that in acute kidney injury (AKI), exogenous ALR can protect renal tubular epithelial cells by inhibiting apoptosis of renal tubular epithelial cells, promoting proliferation of renal tubular epithelial cells, inhibiting the activities of inflammatory cells, and promoting the reduction of renal injury. This paper intends to review the basic characteristics of ALR and the pathogenesis of AKI, summarize the characteristics of the mechanism of ALR in AKI by combing the relevant literature on ALR and AKI in recent years, and provide knowledge reserve and direction reference for the in-depth study of ALR in kidney in the future.

Citation： YU Dan, PU Tao. Research progress of augmenter of liver regeneration in acute kidney injury. West China Medical Journal, 2021, 36(9): 1310-1314. doi: 10.7507/1002-0179.202011222 Copy

1.	Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol, 2013, 8(9): 1482-1493.
2.	Xu X, Nie S, Liu Z, et al. Epidemiology and clinical correlates of AKI in Chinese hospitalized adults. Clin J Am Soc Nephrol, 2015, 10(9): 1510-1518.
3.	de Seigneux S, Martin PY. Preventing the progression of AKI to CKD: the role of mitochondria. J Am Soc Nephrol, 2017, 28(5): 1327-1329.
4.	Doyle JF, Forni LG. Acute kidney injury: short-term and long-term effects. Crit Care, 2016, 20(1): 188.
5.	Kulkarni AP, Bhosale SJ. Epidemiology and pathogenesis of acute kidney injury in the critically ill patients. Indian J Crit Care Med, 2020, 24(Suppl 3): S84-S89.
6.	Peters E, Antonelli M, Wittebole X, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from the Intensive Care Over Nations audit. Crit Care, 2018, 22(1): 188.
7.	Francavilla A, Hagiya M, Porter KA, et al. Augmenter of liver regeneration: its place in the universe of hepatic growth factors. Hepatology, 1994, 20(3): 747-757.
8.	LaBrecque DR, Pesch LA. Preparation and partial characterization of hepatic regenerative stimulator substance (SS) from rat liver. J Physiol, 1975, 248(2): 273-284.
9.	Hagiya M, Francavilla A, Polimeno L, et al. Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demonstration of tissue distribution. Proc Natl Acad Sci USA, 1994, 91(17): 8142-8146.
10.	Gandhi CR, Chaillet JR, Nalesnik MA, et al. Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice. Gastroenterology, 2015, 148(2): 379-391.e4.
11.	Han LH, Dong LY, Yu H, et al. Deceleration of liver regeneration by knockdown of augmenter of liver regeneration gene is associated with impairment of mitochondrial DNA synthesis in mice. Am J Physiol Gastrointest Liver Physiol, 2015, 309(2): G112-G122.
12.	Francavilla A, Vujanovic NL, Polimeno L, et al. The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-Ⅱ on liver natural killer cell functions. Hepatology, 1997, 25(2): 411-415.
13.	Tanigawa K, Sakaida I, Masuhara M, et al. Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases. J Gastroenterol, 2000, 35(2): 112-119.
14.	Liu L, Xie P, Li W, et al. Augmenter of liver regeneration protects against ethanol-induced acute liver injury by promoting autophagy. Am J Pathol, 2019, 189(3): 552-567.
15.	Ai WL, Dong LY, Wang J, et al. Deficiency in augmenter of liver regeneration accelerates liver fibrosis by promoting migration of hepatic stellate cell. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(11): 3780-3791.
16.	廖晓辉. ALR 对大鼠急性肾衰竭中肾小管上皮细胞的生物活性作用研究. 重庆: 重庆医科大学, 2004.
17.	Jha V, Arici M, Collins AJ, et al. Understanding kidney care needs and implementation strategies in low- and middle-income countries: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference. Kidney Int, 2016, 90(6): 1164-1174.
18.	Mercado MG, Smith DK, Guard EL. Acute kidney injury: diagnosis and management. Am Fam Physician, 2019, 100(11): 687-694.
19.	Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med, 2015, 41(8): 1411-1423.
20.	Nath KA, Norby SM. Reactive oxygen species and acute renal failure. Am J Med, 2000, 109(8): 665-678.
21.	Hüttemann M, Helling S, Sanderson TH, et al. Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta, 2012, 1817(4): 598-609.
22.	Re: Yamashita J, Itoh M, Kuro T, Kobayashi Y, Ogata M, Takaoka m, and Matsumura Y (2001) pre- or post-ischemic treatment with a novel Na⁺/Ca²⁺ exchange inhibitor, kb-r7943, shows renal protective effects in rats with ischemic acute renal failure. J pharmacol exp ther 296:412-419. J Pharmacol Exp Ther, 2014, 349(2): 344.
23.	Chi K, Geng X, Liu C, et al. Research progress on the role of inflammasomes in kidney disease. Mediators Inflamm, 2020, 2020: 8032797.
24.	Zilberman-Itskovich S, Abu-Hamad R, Zarura R, et al. Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury. PLoS One, 2019, 14(9): e0222354.
25.	李嵘, 王永星. 药物性肾损害. 世界最新医学信息文摘, 2015, 15(25): 98.
26.	Xia N, Yan RY, Liu Q, et al. Augmenter of liver regeneration plays a protective role against hydrogen peroxide-induced oxidative stress in renal proximal tubule cells. Apoptosis, 2015, 20(4): 423-432.
27.	彭钧渤, 张玲, 龙瑞婷, 等. 肝再生增强因子对横纹肌溶解致大鼠急性肾损伤的保护作用及机制研究. 重庆医科大学学报, 2018, 43(4): 489-493.
28.	张玲, 廖晓辉, 刘杞, 等. 肝再生增强因子在急性肾衰大鼠模型肾组织中的表达及意义. 重庆医学, 2003, 32(6): 647-649.
29.	Fernández M, Medina A, Santos F, et al. Exacerbated inflammatory response induced by insulin-like growth factorⅠtreatment in rats with ischemic acute renal failure. J Am Soc Nephrol, 2001, 12(9): 1900-1907.
30.	唐晓鹏. 肝再生增强因子对庆大霉素诱导急性肾衰大鼠肾小管上皮细胞保护作用及机制研究. 重庆: 重庆医科大学, 2006.
31.	Liao XH, Zhang L, Liu Q, et al. Augmenter of liver regeneration protects kidneys from ischaemia/reperfusion injury in rats. Nephrol Dial Transplant, 2010, 25(9): 2921-2929.
32.	Liao XH, Chen GT, Li Y, et al. Augmenter of liver regeneration attenuates tubular cell apoptosis in acute kidney injury in rats: the possible mechanisms. Ren Fail, 2012, 34(5): 590-599.
33.	Zhu DJ, Liao XH, Huang WQ, et al. Augmenter of liver regeneration protects renal tubular epithelial cells from ischemia-reperfusion injury by promoting PINK1/Parkin-mediated mitophagy. Front Physiol, 2020, 11: 178.
34.	Dai XG, Li T, Huang WB, et al. Upregulation of mitochondrial transcription factor a promotes the repairment of renal tubular epithelial cells in sepsis by inhibiting reactive oxygen species-mediated toll-like receptor 4/p38MAPK signaling. Pathobiology, 2019, 86(5/6): 263-273.
35.	Deng JS, Jiang WP, Chen CC, et al. Cordyceps cicadae Mycelia ameliorate cisplatin-induced acute kidney injury by suppressing the TLR4/NF-κB/MAPK and activating the HO-1/Nrf2 and Sirt-1/AMPK pathways in mice. Oxid Med Cell Longev, 2020: 7912763.
36.	周娟, 张玲, 刘杞, 等. 肝再生增强因子在缺血再灌注肾损伤中的表达及其对p38信号通路的影响. 重庆医科大学学报, 2011, 36(3): 266-269.
37.	Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science, 2003, 300(5625): 1524-1525.
38.	Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol, 2004, 4(7): 499-511.
39.	黎颖. 肝再生增强因子在缺血性急性肾损伤中对 TLR4 信号通路的调控机制研究. 重庆: 重庆医科大学, 2014.
40.	Wang Z, Ying Z, Bosy-Westphal A, et al. Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr, 2010, 92(6): 1369-1377.
41.	O’Connor PM. Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmacol Physiol, 2006, 33(10): 961-967.
42.	Bhargava P, Schnellmann RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol, 2017, 13(10): 629-646.
43.	Thirunavukkarasu C, Wang LF, Harvey SA, et al. Augmenter of liver regeneration: an important intracellular survival factor for hepatocytes. J Hepatol, 2008, 48(4): 578-588.
44.	Mordas A, Tokatlidis K. The MIA pathway: a key regulator of mitochondrial oxidative protein folding and biogenesis. Acc Chem Res, 2015, 48(8): 2191-2199.
45.	Huang LL, Long RT, Jiang GP, et al. Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia-reperfusion injury. Apoptosis, 2018, 23(11-12): 695-706.
46.	Fischer M, Riemer J. The mitochondrial disulfide relay system: roles in oxidative protein folding and beyond. Int J Cell Biol, 2013, 2013: 742923.
47.	Long RT, Peng JB, Huang LL, et al. Augmenter of liver regeneration alleviates renal hypoxia-reoxygenation injury by regulating mitochondrial dynamics in renal tubular epithelial cells. Mol Cells, 2019, 42(12): 893-905.

1. Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol, 2013, 8(9): 1482-1493.
2. Xu X, Nie S, Liu Z, et al. Epidemiology and clinical correlates of AKI in Chinese hospitalized adults. Clin J Am Soc Nephrol, 2015, 10(9): 1510-1518.
3. de Seigneux S, Martin PY. Preventing the progression of AKI to CKD: the role of mitochondria. J Am Soc Nephrol, 2017, 28(5): 1327-1329.
4. Doyle JF, Forni LG. Acute kidney injury: short-term and long-term effects. Crit Care, 2016, 20(1): 188.
5. Kulkarni AP, Bhosale SJ. Epidemiology and pathogenesis of acute kidney injury in the critically ill patients. Indian J Crit Care Med, 2020, 24(Suppl 3): S84-S89.
6. Peters E, Antonelli M, Wittebole X, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from the Intensive Care Over Nations audit. Crit Care, 2018, 22(1): 188.
7. Francavilla A, Hagiya M, Porter KA, et al. Augmenter of liver regeneration: its place in the universe of hepatic growth factors. Hepatology, 1994, 20(3): 747-757.
8. LaBrecque DR, Pesch LA. Preparation and partial characterization of hepatic regenerative stimulator substance (SS) from rat liver. J Physiol, 1975, 248(2): 273-284.
9. Hagiya M, Francavilla A, Polimeno L, et al. Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demonstration of tissue distribution. Proc Natl Acad Sci USA, 1994, 91(17): 8142-8146.
10. Gandhi CR, Chaillet JR, Nalesnik MA, et al. Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice. Gastroenterology, 2015, 148(2): 379-391.e4.
11. Han LH, Dong LY, Yu H, et al. Deceleration of liver regeneration by knockdown of augmenter of liver regeneration gene is associated with impairment of mitochondrial DNA synthesis in mice. Am J Physiol Gastrointest Liver Physiol, 2015, 309(2): G112-G122.
12. Francavilla A, Vujanovic NL, Polimeno L, et al. The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-Ⅱ on liver natural killer cell functions. Hepatology, 1997, 25(2): 411-415.
13. Tanigawa K, Sakaida I, Masuhara M, et al. Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases. J Gastroenterol, 2000, 35(2): 112-119.
14. Liu L, Xie P, Li W, et al. Augmenter of liver regeneration protects against ethanol-induced acute liver injury by promoting autophagy. Am J Pathol, 2019, 189(3): 552-567.
15. Ai WL, Dong LY, Wang J, et al. Deficiency in augmenter of liver regeneration accelerates liver fibrosis by promoting migration of hepatic stellate cell. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(11): 3780-3791.
16. 廖晓辉. ALR 对大鼠急性肾衰竭中肾小管上皮细胞的生物活性作用研究. 重庆: 重庆医科大学, 2004.
17. Jha V, Arici M, Collins AJ, et al. Understanding kidney care needs and implementation strategies in low- and middle-income countries: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference. Kidney Int, 2016, 90(6): 1164-1174.
18. Mercado MG, Smith DK, Guard EL. Acute kidney injury: diagnosis and management. Am Fam Physician, 2019, 100(11): 687-694.
19. Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med, 2015, 41(8): 1411-1423.
20. Nath KA, Norby SM. Reactive oxygen species and acute renal failure. Am J Med, 2000, 109(8): 665-678.
21. Hüttemann M, Helling S, Sanderson TH, et al. Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta, 2012, 1817(4): 598-609.
22. Re: Yamashita J, Itoh M, Kuro T, Kobayashi Y, Ogata M, Takaoka m, and Matsumura Y (2001) pre- or post-ischemic treatment with a novel Na⁺/Ca²⁺ exchange inhibitor, kb-r7943, shows renal protective effects in rats with ischemic acute renal failure. J pharmacol exp ther 296:412-419. J Pharmacol Exp Ther, 2014, 349(2): 344.
23. Chi K, Geng X, Liu C, et al. Research progress on the role of inflammasomes in kidney disease. Mediators Inflamm, 2020, 2020: 8032797.
24. Zilberman-Itskovich S, Abu-Hamad R, Zarura R, et al. Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury. PLoS One, 2019, 14(9): e0222354.
25. 李嵘, 王永星. 药物性肾损害. 世界最新医学信息文摘, 2015, 15(25): 98.
26. Xia N, Yan RY, Liu Q, et al. Augmenter of liver regeneration plays a protective role against hydrogen peroxide-induced oxidative stress in renal proximal tubule cells. Apoptosis, 2015, 20(4): 423-432.
27. 彭钧渤, 张玲, 龙瑞婷, 等. 肝再生增强因子对横纹肌溶解致大鼠急性肾损伤的保护作用及机制研究. 重庆医科大学学报, 2018, 43(4): 489-493.
28. 张玲, 廖晓辉, 刘杞, 等. 肝再生增强因子在急性肾衰大鼠模型肾组织中的表达及意义. 重庆医学, 2003, 32(6): 647-649.
29. Fernández M, Medina A, Santos F, et al. Exacerbated inflammatory response induced by insulin-like growth factorⅠtreatment in rats with ischemic acute renal failure. J Am Soc Nephrol, 2001, 12(9): 1900-1907.
30. 唐晓鹏. 肝再生增强因子对庆大霉素诱导急性肾衰大鼠肾小管上皮细胞保护作用及机制研究. 重庆: 重庆医科大学, 2006.
31. Liao XH, Zhang L, Liu Q, et al. Augmenter of liver regeneration protects kidneys from ischaemia/reperfusion injury in rats. Nephrol Dial Transplant, 2010, 25(9): 2921-2929.
32. Liao XH, Chen GT, Li Y, et al. Augmenter of liver regeneration attenuates tubular cell apoptosis in acute kidney injury in rats: the possible mechanisms. Ren Fail, 2012, 34(5): 590-599.
33. Zhu DJ, Liao XH, Huang WQ, et al. Augmenter of liver regeneration protects renal tubular epithelial cells from ischemia-reperfusion injury by promoting PINK1/Parkin-mediated mitophagy. Front Physiol, 2020, 11: 178.
34. Dai XG, Li T, Huang WB, et al. Upregulation of mitochondrial transcription factor a promotes the repairment of renal tubular epithelial cells in sepsis by inhibiting reactive oxygen species-mediated toll-like receptor 4/p38MAPK signaling. Pathobiology, 2019, 86(5/6): 263-273.
35. Deng JS, Jiang WP, Chen CC, et al. Cordyceps cicadae Mycelia ameliorate cisplatin-induced acute kidney injury by suppressing the TLR4/NF-κB/MAPK and activating the HO-1/Nrf2 and Sirt-1/AMPK pathways in mice. Oxid Med Cell Longev, 2020: 7912763.
36. 周娟, 张玲, 刘杞, 等. 肝再生增强因子在缺血再灌注肾损伤中的表达及其对p38信号通路的影响. 重庆医科大学学报, 2011, 36(3): 266-269.
37. Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science, 2003, 300(5625): 1524-1525.
38. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol, 2004, 4(7): 499-511.
39. 黎颖. 肝再生增强因子在缺血性急性肾损伤中对 TLR4 信号通路的调控机制研究. 重庆: 重庆医科大学, 2014.
40. Wang Z, Ying Z, Bosy-Westphal A, et al. Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr, 2010, 92(6): 1369-1377.
41. O’Connor PM. Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmacol Physiol, 2006, 33(10): 961-967.
42. Bhargava P, Schnellmann RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol, 2017, 13(10): 629-646.
43. Thirunavukkarasu C, Wang LF, Harvey SA, et al. Augmenter of liver regeneration: an important intracellular survival factor for hepatocytes. J Hepatol, 2008, 48(4): 578-588.
44. Mordas A, Tokatlidis K. The MIA pathway: a key regulator of mitochondrial oxidative protein folding and biogenesis. Acc Chem Res, 2015, 48(8): 2191-2199.
45. Huang LL, Long RT, Jiang GP, et al. Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia-reperfusion injury. Apoptosis, 2018, 23(11-12): 695-706.
46. Fischer M, Riemer J. The mitochondrial disulfide relay system: roles in oxidative protein folding and beyond. Int J Cell Biol, 2013, 2013: 742923.
47. Long RT, Peng JB, Huang LL, et al. Augmenter of liver regeneration alleviates renal hypoxia-reoxygenation injury by regulating mitochondrial dynamics in renal tubular epithelial cells. Mol Cells, 2019, 42(12): 893-905.

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