MK-677 alters osmolarity in hypertensive rats, who show lower GHS-R1a expression
Background
Ghrelin is a peptide hormone that exerts its effects via the growth hormone secretagogue receptor subtype 1a (GHS-R1a). While GHS-R1a is most known for its expression in the brain, it is also present in the kidneys, suggesting a role in renal function. Neurogenic hypertension is a form of high blood pressure originating from the nervous system, and the contribution of renal GHS-R1a signaling to its pathophysiology is not well understood. This study hypothesized that the GHS-R1a receptor system is a key player in the kidney's role in developing and maintaining this type of hypertension, potentially through its downregulation affecting renal function and hemodynamics.
Study Design
Researchers used two rat models: normal Wistar (WT) and spontaneously hypertensive rats (SHR). They systemically injected vehicle, ghrelin, the GHS-R1a antagonist PF04628935, ghrelin plus PF04628935, or the synthetic GHS-R1a agonist MK-677. The rats were housed in metabolic cages for 24 hours while blood and urine samples were collected for analysis. The study also assessed the role of GHS-R1a in controlling renal vasomotion and hemodynamics. Finally, GHS-R1a protein levels were quantified in brain areas, aorta, renal artery, renal cortex, and medulla of both WT and SHR rats using western blot.
Results
In spontaneously hypertensive rats (SHR), both ghrelin and MK-677 administration led to changes in osmolarity parameters, and this effect was confirmed to be GHS-R1a-dependent. In contrast, blocking the receptor with an antagonist reduced urinary Na+ and K+ excretion and creatinine clearance in normal Wistar (WT) rats, but surprisingly, not in the SHR model. For hemodynamics, ghrelin administration reduced arterial pressure and increased renal artery conductance specifically in SHR.
The most significant finding was that protein levels of the
GHS-R1areceptor were decreased in both the kidney and various brain areas of SHR when compared to the healthy WT rats.
This downregulation of GHS-R1a in key regulatory organs suggests the receptor's role in managing renal function and blood pressure is altered during neurogenic hypertension, potentially explaining the different responses to receptor activation and antagonism between the healthy and hypertensive models.
Key Findings
- Ghrelin and the GHS-R1a agonist MK-677 altered osmolarity parameters in hypertensive rats (SHR).
- GHS-R1a protein levels were decreased in the kidneys and brain areas of SHR compared to normal Wistar rats (WT).
- GHS-R1a antagonism with PF04628935 reduced urinary Na+ and K+ in WT rats but not in SHR.
- Ghrelin administration reduced arterial pressure and increased renal artery conductance in SHR.
Why It Matters
The findings suggest that the ghrelin system's role in blood pressure and kidney function is significantly different in the context of pre-existing hypertension, which appears linked to a downregulation of GHS-R1a receptors. For individuals with hypertension considering using GHS agonists like MK-677, this implies the response, particularly concerning fluid balance and electrolytes, might be unpredictable or differ from that in healthy individuals. The decreased receptor expression in hypertensive states could mean that standard doses of ghrelin mimetics may have blunted or altered effects. This highlights a potential need for caution and monitoring of renal function and blood pressure for hypertensive individuals using GHS secretagogues. Further research is required to understand if GHS-R1a upregulation could be a therapeutic strategy for neurogenic hypertension, but this is far from a clinical protocol.
TitrateLab articles covering MK-677
Written by TitrateLab, separately from the study summarized above.
