Target molecular mechanisms of litokinetic therapy in nephrolithiasis

BACKGROUND. Mechanisms of ureteral muscularis layer regulation during trafficking of stones in different compartments remain a poorly understood problem in nephrology. AIM of the study was to analyze the activity of the main receptors modulating contraction (α2-adrenoreceptor, purine P2X1and P2Y-receptors, angiotensin AT1-receptor, TR-receptor to TxA2) and smooth myocyte relaxation (adenosine A2-receptor) in the presence of medium and small stones in the urinary tract (UT).

PATIENTS AND METHODS. The study was prospective and included 126 patients with imaging signs of stones in the pyeloureteral compartment of UT (group 1, 61 patients) and in the middle third of the ureter (group 2, 65 patients). The average size of the stones in group 1 was 16.1±1.0 mm (min-max 7.0-25.0 mm), in group 2 – 4.4±0.8 mm (min-max 2.0-6.0 mm). Platelets (Pts) of patients were used as a model for in vitro evaluation of the functional activity of α2-adrenoreceptor, P2X1and P2Y-receptors, AT1-receptor, ТР-receptor and A2-receptor. Pts aggregation was assessed by turbidimetric method on ChronoLog analyser (USA).

RESULTS. The main pathogenic factors of NLT (mechanical damage of mucosa, activation of SAS and RAS, tissue ischemia and alteration, presence of pyelonephritis) influence urinary tract motility, which can be confirmed by the activity of receptors participating in the regulation of smooth muscle cells function detected in vitro on Pts. In the presence of medium-sized stones, the patient's protective response to ensure their elimination is manifested by hyperreactivity of α2-adrenoreceptor, TР-receptor, P2X1-receptor, normoreactivity of P2Y-receptor and AT1-receptor, and hyporesponsiveness of A2A-receptor. In cases of small-sized stones, there was hyperreactivity of α2-adrenoreceptor, AT1-receptor, normoreactivity of P2Y-receptor and A2-receptor and desensitization of P2X1-receptor and TР-receptor.

CONCLUSION. The revealed peculiarities of molecular regulation of target cells in nephrolithiasis require further study in the context of development of personalized schemes of lithokinetic therapy in patients with concrements of different sizes in the urinary tract.

1. Agarwal DK, Krambeck AE, Sharma V et al. Treatment of non-obstructive, non-struvite urolithiasis is effective in treatment of recurrent urinary tract infections. World J Urol 2020;38(8):2029– 2033. doi: 10.1007/s00345-019-02977-3

2. Talamini S, Wong D, Phillips T et al. Improved stone quality of life in patients with an obstructing ureteral stone on alpha-blocker medical expulsive therapy. Int Urol Nephrol 2024;56(4):1289– 1295. doi: 10.1007/s11255-023-03865-x

3. Campschroer T, Zhu X, Vernooij RW, Lock MT. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2018;4(4):CD008509

4. Burdyga T, Lang RJ. Excitation-Contraction Coupling in Ureteric Smooth Muscle: Mechanisms Driving Ureteric Peristalsis. Adv Exp Med Biol 2019;1124:103–119. doi: 10.1007/978-98113-5895-1_4

5. Aksakalli T, Aksakalli IK, Cinislioglu AE et al. Prediction of spontaneous distal ureteral stone passage using artificial intelligence. Int Urol Nephrol 2024;56(7):2179–2186. doi: 10.1007/S11255-024-03955-4

6. Khan SR, Canales BK. Proposal for pathogenesis-based treatment options to reduce calcium oxalate stone recurrence. Asian J Urol 2023;10(3):246–257. doi: 10.1016/j.ajur.2023.01.008

7. Bishop K, Momah T, Ricks J. Nephrolithiasis. Prim Care 2020;47(4):661–671. doi: 10.1016/j.pop.2020.08.005

8. Lawrie AS, Kobayashi K, Lane PJ et al. The automation of routine light transmission platelet aggregation. Int J Lab Hematol 2014;36(4):431–438. doi: 10.1111/ijlh.12161

9. Hernández M, Prieto D, Simonsen U et al. Noradrenaline modulates smooth muscle activity of the isolated intravesical ureter of the pig through different types of adrenoceptors. Br J Pharmacol1992;107(4):924–931. doi: 10.1111/j.1476-5381.1992.tb13387.x

10. Fong Z, Griffin CS, Large RJ A et al. Regulation of P2X1 receptors by modulators of the cAMP effectors PKA and EPAC. Proc Natl Acad Sci U S A 2021 Sep 14;118(37):e2108094118. doi: 10.1073/pnas.2108094118

11. Saad J, Mathew D. Nonsteroidal Anti-Inflammatory Drugs Toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024

12. Nilsson L, Madsen K, Topcu SO et al. Disruption of cyclooxygenase-2 prevents downregulation of cortical AQP2 and AQP3 in response to bilateral ureteral obstruction in the mouse. Am J Physiol Renal Physiol 2012;302(11):F1430–1439. doi: 10.1152/ajprenal.00682.2011

13. Guo Y, Mao T, Fang Y et al. Comprehensive insights into potential roles of purinergic P2 receptors on diseases: Signaling pathways involved and potential therapeutics. J Adv Res 2024:S2090–1232(24)00123-1. doi: 10.1016/j.jare.2024.03.027

14. Hao Y, Wang L, Chen H et al. Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function. JCI Insight 2019;4(16):e122112. doi: 10.1172/jci.insight.122112

15. Aschrafi A, Berndt A, Kowalak JA et al. Angiotensin II mediates the axonal trafficking of tyrosine hydroxylase and dopamine β-hydroxylase mRNAs and enhances norepinephrine synthesis in primary sympathetic neurons. J Neurochem 2019;150(6):666– 677. doi: 10.1111/jnc.14821

16. Cho ST, Park EY, Kim JC. Effect of angiotensin II receptor antagonist telmisartan on detrusor overactivity in rats with bladder outlet obstruction. Urology 2012;80(5):1163.e1–7. doi: 10.1016/j.urology.2012.05.002

17. Comiter CV. Pharmacology in Urology. Urol Clin North Am 2022;49(2):xv. doi: 10.1016/j.ucl.2022.03.001

18. Fillion D, Devost D, Hébert TE. Measuring Recruitment of β-Arrestin to G Protein-Coupled Heterodimers Using Bioluminescence Resonance Energy Transfer. Methods Mol Biol 2019;1957:83–91. doi: 10.1007/978-1-4939-9158-7_5

19. Kishore BK, Robson SC, Dwyer KM. CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal 2018 Jun;14(2):109–120. doi: 10.1007/s11302-017-9596-x