Online first
Original article
Published online: 2024-09-05
Renal structural changes and apelin receptor expression in spontaneously hypertensive rats: implications for hypertension-induced kidney injury
DOI: 10.5603/fm.100637
Pubmed: 39257194
Abstract
Background: Arterial hypertension is a primary risk factor for kidney disease. Recent advances have implied a potential link between the apelin system and renal homeostasis.
Materials and methods: We used 6- and 12-month-old spontaneously hypertensive rats and age-matched normotensive controls to assess the changes in the renal expression of the apelin receptor by immunohistochemical method. The study also evaluated correlations between the renal apelin receptor’s expression and renal injury indicators.
Results: The histological analysis showed elevated glomerular sclerosis and tubulointerstitial damage indices in both groups of hypertensive rats compared to age-matched controls. Older rats within each group exhibited higher scores than younger ones. The immunohistochemical analysis revealed varying apelin receptor expression patterns, with tubular expression intensifying both with hypertension severity and age. Glomerular expression was notably higher in older hypertensive rats compared to normotensive controls. We reported significant positive correlations between glomerular apelin receptor expression and glomerular sclerosis index in older hypertensive animals. Similarly, a positive correlation between tubular apelin receptor expression and tubulointerstitial damage index was discovered in hypertensive rats, suggesting hypertension-related changes in apelin receptor expression and renal damage.
Conclusions: Our study found kidney changes and varying apelin receptor correlations in hypertensive rat kidneys, suggesting complex roles needing research.
Keywords: apelin receptorhypertensionrenal damagechronic kidney diseaseadaptive mechanism
References
- Boulkeroua C, Ayari H, Khalfaoui T, et al. Apelin-13 regulates vasopressin-induced aquaporin-2 expression and trafficking in kidney collecting duct cells. Cell Physiol Biochem. 2019; 53(4): 687–700.
- Braun MC, Herring SM, Gokul N, et al. Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines. J Hypertens. 2013; 31(10): 2050–2059.
- Ceraudo E, Galanth C, Carpentier E, et al. Biased signaling favoring gi over β-arrestin promoted by an apelin fragment lacking the C-terminal phenylalanine. J Biol Chem. 2014; 289(35): 24599–24610.
- Nyimanu D, Chapman FA, Gallacher PJ, et al. The therapeutic potential of apelin in kidney disease. Nat Rev Nephrol. 2021; 17(12): 840–853.
- Charo DN, Ho M, Fajardo G, et al. Endogenous regulation of cardiovascular function by apelin-APJ. Am J Physiol Heart Circ Physiol. 2009; 297(5): H1904–H1913.
- Chatziantoniou C, Boffa JJ, Tharaux PL, et al. Progression and regression in renal vascular and glomerular fibrosis. Int J Exp Pathol. 2004; 85(1): 1–11.
- Folino A, Montarolo PG, Samaja M, et al. Effects of apelin on the cardiovascular system. Heart Fail Rev. 2015; 20(4): 505–518.
- Gerbier R, Leroux V, Couvineau P, et al. New structural insights into the apelin receptor: identification of key residues for apelin binding. FASEB J. 2015; 29(1): 314–322.
- Girault-Sotias PE, Gerbier R, Flahault A, et al. Apelin and Vasopressin: The Yin and Yang of Water Balance. Front Endocrinol (Lausanne). 2021; 12: 735515.
- Gurzu B, Petrescu BC, Costuleanu M, et al. Interactions between apelin and angiotensin II on rat portal vein. J Renin Angiotensin Aldosterone Syst. 2006; 7(4): 212–216.
- Hosoya M, Kawamata Y, Fukusumi S, et al. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem. 2000; 275(28): 21061–21067.
- Hultström M. Development of structural kidney damage in spontaneously hypertensive rats. J Hypertens. 2012; 30(6): 1087–1091.
- Hus-Citharel A, Bodineau L, Frugière A, et al. Apelin counteracts vasopressin-induced water reabsorption via cross talk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Endocrinology. 2014; 155(11): 4483–4493.
- Hus-Citharel A, Bouby N, Frugière A, et al. Effect of apelin on glomerular hemodynamic function in the rat kidney. Kidney Int. 2008; 74(4): 486–494.
- Ishida J, Hashimoto T, Hashimoto Y, et al. Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J Biol Chem. 2004; 279(25): 26274–26279.
- Iturrioz X, Gerbier R, Leroux V, et al. By interacting with the C-terminal Phe of apelin, Phe255 and Trp259 in helix VI of the apelin receptor are critical for internalization. J Biol Chem. 2010; 285(42): 32627–32637.
- Kotov G, Landzhov B, Stamenov N, et al. Changes in the number of mast cells, expression of fibroblast growth factor-2 and extent of interstitial fibrosis in established and advanced hypertensive heart disease. Ann Anat. 2020; 232: 151564.
- Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996; 334(15): 939–945.
- Meyrier A. Nephrosclerosis: update on a centenarian. Nephrol Dial Transplant. 2015; 30(11): 1833–1841.
- Müller T, Kalea AZ, Marquez A, et al. Apelinergic system in the kidney: implications for diabetic kidney disease. Physiol Rep. 2018; 6(23): e13939.
- Murray CJL, Lopez AD. Measuring the global burden of disease. N Engl J Med. 2013; 369(5): 448–457.
- Nishida M, Okumura Y, Oka T, et al. The role of apelin on the alleviative effect of Angiotensin receptor blocker in unilateral ureteral obstruction-induced renal fibrosis. Nephron Extra. 2012; 2(1): 39–47.
- Nogueira A, Pires MJ, Oliveira PA. Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In Vivo. 2017; 31(1): 1–22.
- O'Carroll AM, Salih S, Griffiths PR, et al. Expression and functional implications of the renal apelinergic system in rodents. PLoS One. 2017; 12(8): e0183094.
- O'Carroll AM, Selby TL, Palkovits M, et al. Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues. Biochim Biophys Acta. 2000; 1492(1): 72–80.
- O'Dowd BF, Heiber M, Chan A, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene. 1993; 136(1-2): 355–360.
- Rai R, Ghosh AK, Eren M, et al. Downregulation of the apelinergic axis accelerates aging, whereas its systemic restoration improves the mammalian healthspan. Cell Rep. 2017; 21(6): 1471–1480.
- Schreiber CA, Holditch SJ, Generous A, et al. Sustained ELABELA gene therapy in high-salt diet-induced hypertensive rats. Curr Gene Ther. 2017; 16(5): 349–360.
- Sekerci R, Acar N, Tepekoy F, et al. Apelin/APJ expression in the heart and kidneys of hypertensive rats. Acta Histochem. 2018; 120(3): 196–204.
- Siddiquee K, Hampton J, McAnally D, et al. The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. Br J Pharmacol. 2013; 168(5): 1104–1117.
- Sievers LK, Eckardt KU. Molecular mechanisms of kidney injury and repair in arterial hypertension. Int J Mol Sci. 2019; 20(9).
- Stanchev S, Landzhov B, Kotov G, et al. The potential role of mast cells and fibroblast growth factor-2 in the development of hypertension-induced renal damage. Acta Histochem. 2020; 122(6): 151599.
- Sun X, Iida S, Yoshikawa A, et al. Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely. Hypertens Res. 2011; 34(6): 701–706.
- Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006; 55(1): 225–233.
- Treuting PM, Dintzis SM, Montine KS. Comparative anatomy and histology: a mouse, rat, and human atlas. Academic Press, London 2017.
- Varghese F, Bukhari AB, Malhotra R, et al. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One. 2014; 9(5): e96801.
- Wang LY, Diao ZL, Zhang DL, et al. The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis. Amino Acids. 2014; 46(12): 2693–2704.
- Wang M, Han W, Zhang M, et al. Long-term renal sympathetic denervation ameliorates renal fibrosis and delays the onset of hypertension in spontaneously hypertensive rats. Am J Transl Res. 2018; 10(12): 4042–4053.
- Wang Y, Huang J, Liu Xi, et al. β-Arrestin-biased AT1R stimulation promotes extracellular matrix synthesis in renal fibrosis. Am J Physiol Renal Physiol. 2017; 313(1): F1–F8.
- Whelton PK, Carey RM, Aronow WS. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018; 71(6): 1269–1324.
- Xu C, Wang F, Chen Y, et al. ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury. Am J Physiol Renal Physiol. 2020; 318(5): F1122–F1135.
- Xu T, Jia J, Xu Na, et al. Apelin receptor upregulation in spontaneously hypertensive rat contributes to the enhanced vascular smooth muscle cell proliferation by activating autophagy. Ann Transl Med. 2021; 9(8): 627.
- Xue HY, Yuan Li, Cao YJ, et al. Resveratrol ameliorates renal injury in spontaneously hypertensive rats by inhibiting renal micro-inflammation. Biosci Rep. 2016; 36(3).
- Zhao W, Chen SS, Chen Y, et al. Kidney fibrosis in hypertensive rats: role of oxidative stress. Am J Nephrol. 2008; 28(4): 548–554.
- Zhong JC, Yu XY, Huang Yu, et al. Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res. 2007; 74(3): 388–395.
