Identification of a Forskolin-Like Molecule in Human Renal Cysts

Abstract

Renal cyst enlargement is increased by adenosine cAMP, which is produced within mural epithelial cells. In a search for modulators of cAMP synthesis cyst fluids from 18 patients with autosomal dominant or recessive polycystic kidney disease (PKD) were analyzed, and in 15 of them, a stable lipophilic molecule that increased cAMP levels, stimulated transepithelial chloride and fluid secretion, and promoted the proliferation of human cyst epithelial cells was characterized. With the use of HPLC-mass spectrometry, a bioactive lipid with the same mass spectral fingerprint, the same chromatographic retention time, and the same biologic properties as forskolin, a widely known, potent adenylyl cyclase agonist, has been isolated and identified within the cyst fluid. Forskolin is synthesized by the plant Coleus forskohlii, but its appearance or compounds like it have not been reported in animals. The origin of forskolin in patients with PKD was not revealed by this study. Synthesis by mural cyst epithelial cells or an exogenous source are the most likely possibilities. Forskolin is sold for weight management and as a cardiovascular tonic in health stores and through the Worldwide Web. It is concluded that forskolin may have a role in promoting the enlargement of cysts in autosomal dominant PKD and recommended that patients avoid oral and parenteral preparations that contain this compound.

Periostin induces proliferation of human autosomal dominant polycystic kidney cells through αV-integrin receptor

“…Total surface area (SA) of cysts (Ն 100 m) per well was determined with a video analysis system attached to an inverted microscope. Forskolin, a direct activator of adenylyl cyclase, stimulated cAMP-dependent cell proliferation and fluid secretion (36,50). PN alone had no effect of cyst expansion; however, PN amplified the effect of forskolin.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Reports on the occurrence of an endogenous FSK-like molecule have not yet been confirmed (Putnam et al, 2007). Thus, the physiologic relevance of the FSK binding site is still elusive.…”

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

“…30 (4) Other contributory factors include disruption of PC1 binding to heterotrimeric G proteins, upregulation of the vasopressin V2 receptor, and increased levels of circulating vasopressin or accumulation of forskolin, lisophosphatidic acid, ATP, or other adenylyl cyclase agonists in the cyst fluid. [42][43][44][45][46] The marked amelioration of the cystic disease in collecting ductspecific Pkd1 knockout mice by a concomitant AC6 knockout provides strong support to the central role of calciuminhibitable AC6. 47 PDEs are likely important in PKD, because maximal rates of degradation by PDEs exceed by one order of magnitude those rates of synthesis by ACs and hence, control compartmentalized pools of cAMP that are likely more crucial than total intracellular cAMP.…”