Role of carbon monoxide in kidney function: is a little carbon monoxide good for the kidney?

Abstract

Carbon monoxide (CO) is an endogenously produced gas resulting from the degradation of heme by heme oxygense or from fatty acid oxidation. Heme oxygenase (HO) enzymes are constitutively expressed in the kidney (HO-2) and HO-1 is induced in the kidney in response to several physiological and pathological stimuli. While the beneficial actions of HO in the kidney have been recognized for some time, the important role of CO in mediating these effects has not been fully examined. Recent studies using CO inhalation therapy and carbon monoxide releasing molecules (CORMs) have demonstrated that increases in CO alone can be beneficial to the kidney in several forms of acute renal injury by limiting oxidative injury, decreasing cell apoptosis, and promoting cell survival pathways. Renal CO is also emerging as a major regulator of renal vascular and tubular function acting to protect the renal vasculature against excessive vasoconstriction and to promote natriuresis by limiting sodium reabsorption in tubule cells. Within this review, recent studies on the physiological actions of CO in the kidney will be explored as well as the potential therapeutic avenues that are being developed targeting CO in the kidney which may be beneficial in diseases such as acute renal failure and hypertension.

Figure 1

Carbon monoxide (CO) signaling in the kidney. Carbon monoxide is mainly generated through metabolism of heme by heme oxygenase as well as a by-product of lipid peroxidation. CO mainly signals through activation of soluble guanylate cyclase (sGC) which increase cellular cGMP levels. CO can also inhibit cystolic NADPH oxidase to limit superoxide formation (0₂^.) while promoting superoxide formation in mitochondria. CO has both stimulatory as well as inhibitory actions on nitric oxide (NO) and inhibits inflammation and apoptosis via activation of mitogen activated protein kinase (MAPK), Phosphoinositide 3-kinase (PI3K)/Atk and peroxisome proliferator-activated receptor γ (PPAR-γ).

Figure 2

Effect of carbon monoxide releasing molecules (CORMs), CORM-3, and CORM-A1 on mortality and plasma creatinine in C57BL/6J mice treated with cisplatin. A) Kaplan–Meier survival curve of mice after injection of cisplatin (CP) and subsequent treatment with vehicle, CORM-3, inactive CORM-3 (iCORM-3), and CORM-A1 (n=8). Treatment with CORM-3 and CORM-A1 increased the survival rate as compared to untrated (CP) and iCORM-3 treated mice. B) Plasma creatinine levels in mice following CP treatment. Treatment with CORM-3 and CORM-A1 significantly blunted the increase in plasma creatinine as compared to CP treated mice, n=8. *= statistically significant P< 0.05 as compared to CP treated mice.

Figure 3

Schematic diagram summarizing the effect of CO on A) the renal vasculature and B) renal tubules. In the vasculature, CO can cause vasodilatation through increases in cGMP via stimulation of soluble guanylate cyclase (sGC). The increase in cGMP levels results in activation of the large conductance calcium activated potassium channel (KCa). Both CO and NO can also directly activate KCa channels. Low levels of CO also stimulate NO which leads to activation of KCa via increases in cGMP. However, high levels of CO can inhibit NO production in the vasculature and cause vasoconstriction. In renal tubules, CO inhibits superoxide (0₂^.) production to decrease the activity of the sodium-potassium-2 chloride transporter (NKCC2) in the thick ascending loop of Henle (TALH). Superoxide also decreases NO levels. NO is an endogenous inhibitor of NKCC2 via cGMP mediated decreases in apical insertion of the transporter. CO may also have a direct effect on the NKCC2 transporter to decreases its activity resulting in a decrease in sodium reabsorption in the TALH.