Long-Term Betaine Supplementation Increases Creatinine Clearance and Upregulates MAS and AT2 Receptor Expression in Spontaneously Hypertensive Rat Kidneys

Hypertension contributes to renal dysfunction, partly through dysregulation of the renin-angiotensin system (RAS). Betaine, an osmolyte that helps maintain medullary osmotic gradients, has demonstrated renoprotective effects in models of nephrotoxicity. Previously, we showed that acute betaine administration increases diuresis-more pronounced in spontaneously hypertensive rats (SHRs) than in normotensive Wistar-Kyoto rats-without affecting blood pressure. In this study, we investigate the effects of chronic betaine supplementation on SHR renal function. METHODS: Six-week-old, male SHRs received either 0.5% betaine in drinking water or tap water for 16 weeks. Hemodynamics, serum and urine biochemistry, and renal mRNA expression of RAS components and betaine transporters (SLC6A12, SLC6A20) were assessed. RESULTS: Betaine-treated SHRs demonstrated higher creatinine clearance without significant changes in arterial blood pressure. Renal expression of angiotensinogen and AT1B receptor was reduced, while MAS and AT2 receptor expression increased. Transporter expression showed region-specific regulation: cortical SLC6A20 and medullary SLC6A12 were lower in betaine-treated rats, whereas medullary SLC6A20 was higher. CONCLUSION: Chronic betaine supplementation was associated with increased creatinine clearance and a renal RAS mRNA profile shifted toward MAS and AT2 receptor predominance. These findings support further investigation of betaine as a potential strategy for early prevention of hypertensive kidney injury. However, direct evidence of improved glomerular filtration and functional activation of protective RAS pathways is still needed.