Abstract
Opioid use is associated with predictors of poor cardiorenal outcomes. However, little is known about the direct impact of opioids on podocytes and renal function, especially in the context of hypertension and CKD. We hypothesize that stimulation of opioid receptors (ORs) contributes to dysregulation of intracellular calcium ([Ca2+]i) homeostasis in podocytes, thus aggravating the development of renal damage in hypertensive conditions. Herein, freshly isolated glomeruli from Dahl salt-sensitive (SS) rats and human kidneys, as well as immortalized human podocytes, were used to elucidate the contribution of specific ORs to calcium influx. Stimulation of κ-ORs, but not μ-ORs or δ-ORs, evoked a [Ca2+]i transient in podocytes, potentially through the activation of TRPC6 channels. κ-OR agonist BRL52537 was used to assess the long-term effect in SS rats fed a high-salt diet. Hypertensive rats chronically treated with BRL52537 exhibited [Ca2+]i overload in podocytes, nephrinuria, albuminuria, changes in electrolyte balance, and augmented blood pressure. These data demonstrate that the κ-OR/TRPC6 signaling directly influences podocyte calcium handling, provoking the development of kidney injury in the opioid-treated hypertensive cohort.
Highlights
Excessive opioid use has become a global health concern, yet very little is known about how it affects renal function in chronic kidney disease (CKD) or hypertension
Podocytes of freshly isolated glomeruli were loaded with calcium fluorescent indicators (Fluo4/Fura 2TH) and used to test the contribution of opioid receptors (ORs) to the calcium homeostasis by confocal microscopy (Fig 1A)
Pre-application of SAR7334 (100 nM), a specific TRPC6 channel inhibitor (Maier et al, 2015; Ilatovskaya et al, 2017), significantly attenuated the effect of κ-OR–mediated calcium influx in cultured podocytes, reducing the amplitude of the signal to the levels observed in 0 mM [Ca2+]out (Fig 2E)
Summary
Excessive opioid use has become a global health concern, yet very little is known about how it affects renal function in chronic kidney disease (CKD) or hypertension. The extensive use of opioid-based pain management strongly correlates with poor cardiovascular and cardiorenal outcomes, including increased albuminuria and reduced glomerular filtration rate (Agodoa et al, 2008; Mallappallil et al, 2017); as such, opioid medication is strongly linked to progressive renal damage and blood pressure elevation (Herzig et al, 2014; Barbosa-Leiker et al, 2016). Opioid overdose is a huge problem in pain management, especially in patients with CKD. Because more than 17% of Americans had at least one opioid prescription filled, the need for improvements in pain management, especially in those with CKD and hypertension, has risen
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