Increased cAMP in proximal tubules is acute effect of nicotinamide analogues

Abstract

The possible role of adenosine 3',5'-cyclic monophosphate (cAMP) in the mechanism of the acute inhibitory effects of nicotinamide and analogues on brush-border membrane (BBM) phosphate transport was investigated. Compared with basal values, cAMP content of rat renal proximal tubule suspensions was elevated two- to fivefold when incubated at 37 degrees C for 1 h with nicotinamide, 5-methylnicotinamide, or picolinamide at 1-3 mM and in the presence of a phosphodiesterase inhibitor. Thymidine had no effect on cAMP content. There was significant and specific inhibition of BBM transport of phosphate when proximal tubules were incubated with either nicotinamide or picolinamide at concentrations that increased tubule cAMP content. Thymidine had no effect on BBM transport of phosphate. These findings were independent of the dietary Pi intake of the rats. The absence of any effect of thymidine on phosphate transport strongly suggests that inhibition of poly(adenosine diphosphate ribose) polymerase does not play a role in nicotinamide action on phosphate transport. The change in phosphate transport induced by nicotinamide occurred with no change in NAD content. These findings indicate that an increase in cAMP, rather than NAD, is the important change that may mediate the acute inhibition of Na(+)-dependent phosphate transport by nicotinamide.

Host Targeted Activity of Pyrazinamide in Mycobacterium tuberculosis Infection

“…Our present results suggest that similar to our observations with PDE4i, the contribution of PZA to TB therapy may also be derived from its modulation of inflammation via a cAMP-mediated mechanism, in addition to its direct antimicrobial activity [39], [40]. Furthermore, the observed anti-inflammatory activity of PZA may be associated with the previously reported inhibition of pro-inflammatory cytokines by nicotinamide, an analogue of PZA [41], [42] and a potent PDE4i that has been shown to increase the intracellular levels of cAMP [43], [44].…”

A case of familial tumoral calcinosis/hyperostosis–hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features

“…(20,21) Niacinamide is a B-complex vitamin that is converted to nicotinamide adenosine dinucleotide (NAD) and nicotinamide adenosine dinucleotide phosphate (NADP), which are coenzymes for many oxidation-reduction reactions. Nicotinamide and its analogues, similar to PTH, increase intracellular cAMP in kidney cells, and it is through this mechanism that it is believed to decrease renal phosphate reabsorption.…”

“…Nicotinamide and its analogues, similar to PTH, increase intracellular cAMP in kidney cells, and it is through this mechanism that it is believed to decrease renal phosphate reabsorption. (20) Acetazolamide is an inhibitor of the enzyme carbonic anhydrase, which, like PTH, increases renal cell cAMP and is believed to result in phosphaturia by via this mechanism. (21) There are reports in the literature wherein long term administration of acetazolamide appeared to be useful for the treatment of tumoral calcinosis resistant to phosphorus deprivation by aluminum hydroxide alone.…”

Inhibition of phosphate transport by NAD+/NADH in brush border membrane vesicles

“…NAD + and NADH control Pi homeostasis indirectly, most likely through increased cAMP, redox status, etc. [14,18,19,21,23]. However, Prof. Thomas Dousa's group reported forty years ago that these dinucleotides also directly inhibit the Pi transport systems located in the apical membranes of intestinal and renal epithelia [15,16,24].…”

“…By acting on the intestine, NAM is also able to reduce hyperphosphatemia in the experimental adenine-induced CKD model in rats [18]. The non-competitive, inhibitory mechanisms of NAM on Pi transport inhibition seem to be mediated by the increased generation of NAD + through Nampt activity [13,14], while previous works had discarded this possibility and had instead indicated an increased cAMP content in renal proximal tubule suspensions [19,20] or even an oxidative effect and redox status modification [21].…”