Mycophenolate Mofetil Attenuates DOCA-Salt Hypertension: Effects on Vascular Tone

Abstract

Inflammation is increasingly recognized as a driver of hypertension. Both genetic and pharmacological inhibition of B and T cells attenuates most forms of experimental hypertension. Accordingly, the immunosuppressive drug mycophenolate mofetil (MMF) reduces blood pressure in the deoxycorticosterone acetate (DOCA-) salt model. However, the mechanisms by which MMF prevent hypertension in the DOCA-salt model remain unclear. Recent studies indicate that immunosuppression can inhibit sodium transporter activity in the kidney, but its effect on vascular tone is not well characterized. Therefore, the aim of the present study was to analyze the vascular and renal tubular effects of MMF in the DOCA-salt model in rats (4 weeks without uninephrectomy). Co-treatment with MMF attenuated the rise in blood pressure from day 11 onward resulting in a significantly lower telemetric mean arterial pressure after 4 weeks of treatment (108 ± 7 vs. 130 ± 9 mmHg, P < 0.001 by two-way analysis of variance). MMF significantly reduced the number of CD3+ cells in kidney cortex and inner medulla, but not in outer medulla. In addition, MMF significantly reduced urinary interferon-γ excretion. Vascular tone was studied ex vivo using wire myographs. An angiotensin II type 2 (AT2) receptor antagonist blocked the effects of angiotensin II (Ang II) only in the vehicle group. Conversely, L-NAME significantly increased the Ang II response only in the MMF group. An endothelin A receptor blocker prevented vasoconstriction by endothelin-1 in the MMF but not in the vehicle group. MMF did not reduce the abundances of the kidney sodium transporters NHE3, NKCC2, NCC, or ENaC. Together, our ex vivo results suggest that DOCA-salt induces AT2 receptor-mediated vasoconstriction. MMF prevents this response and increases nitric oxide availability. These data provide insight in the antihypertensive mechanism of MMF and the role of inflammation in dysregulating vascular tone.

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

“…Abundant evidence has demonstrated the association between gut dysbiosis, the immune system, and hypertension [1,3,4,11,43]. Our results are consistent with data previously described, with MMF being able to prevent BP increase [17,18] and improve aortic endothelial dysfunction, increasing NO availability in DOCA-salt animals [18]. Furthermore, we found that the MMF treatment induced a modulation in the aortic immune cell infiltration, inducing a reduction in the pro-inflammatory and pro-oxidative cytokine profile.…”

“…As was described previously [18], chronic MMF treatment showed a progressive decrease in SBP ( Figure 5A), which was significant after 2 weeks of treatment, reaching a total reduction of 22.3 ± 3.4 mmHg in the DOCA-salt group. MMF induced a significant reduction of left ventricular hypertrophy (≈13%) in the DOCA-salt group ( Figure 5B).…”

“…In fact, the increase in acetate-producing bacteria induced by high-fiber diet, Bifidobacterium breve consumption, or acetate supplementation were associated with decreased BP, improvement of vascular endothelial and cardiac dysfunction, and attenuation of cardiac and renal fibrosis in DOCA-salt animals [8,9]. BP-lowering effects of MMF have been associated with decreased circulating and renal T cells in SHR and DOCA-salt rats, although MMF reduced both T cell subtypes, Th17 and Tregs [17,18,46]. However, we found increased Tregs and IL-10 (the main cytokine produced by Treg) in both MLNs and aortas of MMF-treated rats, which could contribute to their antihypertensive effects, since IL-10 released by Tregs improves endothelial function and reduces BP in hypertensive mice [28].…”

“…This drug depletes proliferating B and T lymphocytes and macrophages due to its ability to rate-limit enzymes in de novo synthesis of guanosine nucleotides. MMF was able to prevent the development of hypertension in DOCA-salt due to pharmacological inhibition of B and T cell proliferation [17,18]. Recently, it has been described that MMF influences the gut microbiome in renal transplant patients [19][20][21][22] and rodents [23].…”

Arterial Hypertension and Interleukins: Potential Therapeutic Target or Future Diagnostic Marker?

“…Moreover, in SLE mice receiving treatment with MMF, CD45R + B cells depletion with subsequent autoantibody production inhibition was observed. These findings are connected to a previous study that linked autoimmunity with HTN development [181]. Hypertensive patients tend to have an increased level of AT1R antibodies, α -adrenergic receptors, and L-type voltage gated calcium channels [180–183].…”