Gasotransmitters for the Therapeutic Prevention of Hypertension and Kidney Disease

Abstract

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), three major gasotransmitters, are involved in pleiotropic biofunctions. Research on their roles in hypertension and kidney disease has greatly expanded recently. The developing kidney can be programmed by various adverse in utero conditions by so-called renal programming, giving rise to hypertension and kidney disease in adulthood. Accordingly, early gasotransmitter-based interventions may have therapeutic potential to revoke programming processes, subsequently preventing hypertension and kidney disease of developmental origins. In this review, we describe the current knowledge of NO, CO, and H2S implicated in pregnancy, including in physiological and pathophysiological processes, highlighting their key roles in hypertension and kidney disease. We summarize current evidence of gasotransmitter-based interventions for prevention of hypertension and kidney disease in animal models. Continued study is required to assess the interplay among the gasotransmitters NO, CO, and H2S and renal programming, as well as a greater focus on further clinical translation.

Sodium Thiosulfate Improves Hypertension in Rats with Adenine-Induced Chronic Kidney Disease

“…However, the extent to which the organ-specific expression of NO synthase enzymes was affected by STS awaits further evaluation. Notably, previous studies have revealed cross-talk mechanisms between H 2 S, NO, and carbon monoxide (CO) against hypertension [ 4 , 6 ]. H 2 S can modify cysteine residues on key signaling molecules such as nuclear factor erythroid 2-related factor 2 (NRF2) and nuclear factor κB (NFκB), thereby promoting antioxidant and anti-inflammatory effects [ 6 ].…”

“…Emerging evidence suggests that a reduction in H 2 S synthesis may be a key mechanism underlying hypertension and kidney disease [ 1 , 2 , 4 ]. In the kidneys, a mismatch of vasodilators, such as H 2 S and nitric oxide (NO), and vasoconstrictors, such as angiotensin II (Ang II), in favor of the latter, may ultimately lead to hypertension [ 5 , 6 ]. Conversely, H 2 S-based modalities have been developed for therapeutic protection against hypertension and kidney disease [ 6 , 7 ].…”

Chronic Kidney Disease: Strategies to Retard Progression

“…Moreover, a single episode of severe AKI superimposed on patients with pre-existing CKD can cause further renal deterioration to end-stage kidney disease (ESKD) rapidly at a non-linear pace ( Figure 1 B). The risk factors associated with the AKI-related acceleration of renal progression were identified previously, and include older age, delayed renal function recovery from AKI, severe AKI episodes, the presence of proteinuria, and comorbidities such as DM, hypertension, and heart failure [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , ...…”

“…Besides lifestyle modifications, including salt restriction, smoking cessation, weight loss, and adequate exercise, pharmacotherapy can be beneficial with the use of renoprotective agents, including RAAS blockades and carvedilol [ 80 , 81 , 82 ]. Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, are able to reduce proteinuria and BP, but are limited in the treatment of CKD due to their association with GFR decline and hyperkalemia [ 83 , 84 , 85 ].…”

The First Thousand Days: Kidney Health and Beyond

“…Likewise, RAS-based interventions have also shown promising results in protecting against renal programming and related diseases, such as renin inhibitor, ACE inhibitor, ACE-2 (ACE2) activator, and ARBs [111]. Furthermore, reprogramming interventions targeting the hydrogen sulfide (H 2 S) pathway [146] and nutrient-sensing signals [147] have also shown benefits with regard to kidney disease of developmental origin. Although significant advances have been made from animal research, the need for meaningful clinical translation remains a research priority.…”