Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

Abstract

The nephron is the functional unit of the kidney. Blood and plasma are continually filtered within the glomeruli that begin each nephron. Adenosine 5′ triphosphate (ATP) and its metabolites are freely filtered by each glomerulus and enter the lumen of each nephron beginning at the proximal convoluted tubule (PCT). Flow rate, osmolality, and other mechanical or chemical stimuli for ATP secretion are present in each nephron segment. These ATP-release stimuli are also different in each nephron segment due to water or salt permeability or impermeability along different luminal membranes of the cells that line each nephron segment. Each of the above stimuli can trigger additional ATP release into the lumen of a nephron segment. Each nephron-lining epithelial cell is a potential source of secreted ATP. Together with filtered ATP and its metabolites derived from the glomerulus, secreted ATP and adenosine derived from cells along the nephron are likely the principal two of several nucleotide and nucleoside candidates for renal autocrine and paracrine ligands within the tubular fluid of the nephron. This minireview discusses the first principles of purinergic signaling as they relate to the nephron and the urinary bladder. The review discusses how the lumen of a renal tubule presents an ideal purinergic signaling microenvironment. The review also illustrates how remodeled and encapsulated cysts in autosomal dominant polycystic kidney disease (ADPKD) and remodeled pseudocysts in autosomal recessive PKD (ARPKD) of the renal collecting duct likely create an even more ideal microenvironment for purinergic signaling. Once trapped in these closed microenvironments, purinergic signaling becomes chronic and likely plays a significant epigenetic and detrimental role in the secondary progression of PKD, once the remodeling of the renal tissue has begun. In PKD cystic microenvironments, we argue that normal purinergic signaling within the lumen of the nephron provides detrimental acceleration of ADPKD once remodeling is complete.

Ectophosphodiesterase/nucleotide phosphohydrolase (Enpp) nucleotidases: cloning, conservation and developmental restriction

“…This is consistent with the expression in that organ of LPA2, LPA4 and S1P1-4, bioactive lipid receptors (Contos et al, 2000;Awad et al, 2006) and also with the importance of the purinoreceptors (reviewed in Unwin et al, 2003), whose misexpression has been implicated in polycystic kidney disease (Turner et al, 2004). Purinergic signalling plays essential roles in both normal renal physiology and pathological renal cases (reviewed in Hovater et al, 2008).…”

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.…”

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

“…[10][11][12] It is accepted that the CD cells elevate [Ca 2+ ] i in response to mechanical stress arising from variations in tubular flow or tubular composition. [13][14][15][16][17][18][19][20][21][22][23] Impaired mechanosensitive [Ca 2+ ] i responses, reported for both cultured ADPKD 24 and ARPKD 25,26 cells, point to a possible fundamental role of disrupted [Ca 2+ ] i signaling in cystogenesis. The central cilia and cilia-associated PC1 and PC2 were proposed to mediate flow-induced cellular responses.…”