Polycystic kidney diseases (PKD) are a group of inherited nephropathies characterized by the formation of fluid-filled cysts along the nephron. Autosomal Recessive form of PKD (ARPKD) has an incidence of 1 in 20,000 live births; infants with this disease that survive beyond the perinatal period develop chronic renal failure by adolescence and eventually require kidney transplantation. This proposal focuses on the sodium transport regulation in the renal collecting ducts in ARPKD and potential means of pharmacological intervention with the cysts' progression. Specifically, we have determined that Epithelial Sodium Channels (ENaCs), which are expressed in the collecting ducts and represent the rate-limiting step of sodium reabsorption in this nephron segment, are involved into the process of cystogenesis in the ARPKD setting. Our preliminary data indicate that ENaC expression and activity are significantly lower in the cystic epithelial cells of a rat model of ARPKD, as assessed with immunohistochemistry and single channel analysis in isolated cysts; furthermore, chronic administration of the ENaC-specific inhibitor, benzamil, aggravated cyst formation. Thus, we propose that ENaC inhibition exacerbates PKD progression. Using a novel enzymatic microbiosensors approach we established that concentration of adenosine triphosphate (ATP) was significantly higher in PCK rat cortical cysts compared to control rats. ATP was shown to inhibit ENaC via signaling cascades initiated by binding to its receptors. Therefore, we hypothesize here that accumulation of excessive levels of ATP in the lumen of the dilated collecting ducts affects specific purinergic receptors in the cystic cells (primary candidates being P2Y2 or P2X7) and results in ENaC inhibition; this suppresses normal sodium reabsorption in these collecting ducts, and thus promotes fluid accumulation and cysts' expansion. The integrative experimental approach used in this study will include single nephron electrophysiology, in vivo animal studies, genetics, biochemistry, biosensors amperometry and confocal microscopy and will address the clinically relevant problem of cyst expansion in ARPKD. Specifically, this proposal will identify the involvement of the ATP- triggered signaling into regulation of sodium reabsorption in this setting. This proposal will address the following specific aims: 1. Determine the relationship between ENaC activity and cystogenesis in ARPKD; 2. Elucidate the cellular and molecular mechanism by which excessive levels of ATP modulate sodium transport, promoting cyst growth; and 3. Explore if P2 receptor agonists/antagonists and suppression of the ATP levels can affect cystogenesis.
Autosomal recessive form of the polycystic kidney disease (ARPKD) is a genetic disorder that has an incidence of 1 in 20,000 live births; infants affected with this disorder, if survive beyond the perinatal period, develop chronic renal failure by adolescence and eventually require kidney transplantation. The project is focused on the role of renal sodium reabsorption in the mechanism of this disease development. Anticipated results will provide novel therapeutic targets potentially useful for the treatment of the disease.
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| Pavlov, Tengis S; Levchenko, Vladislav; Ilatovskaya, Daria V et al. (2017) Lack of Effects of Metformin and AICAR Chronic Infusion on the Development of Hypertension in Dahl Salt-Sensitive Rats. Front Physiol 8:227 |
| Staruschenko, Alexander; Ilatovskaya, Daria V; Pavlov, Tengis S (2016) High salt diet and caffeine: food for thought. J Thorac Dis 8:E1410-E1412 |
| Palygin, Oleg; Ilatovskaya, Daria V; Staruschenko, Alexander (2016) Protease-activated receptors in kidney disease progression. Am J Physiol Renal Physiol 311:F1140-F1144 |
| Ilatovskaya, Daria V; Palygin, Oleg; Staruschenko, Alexander (2016) Functional and therapeutic importance of purinergic signaling in polycystic kidney disease. Am J Physiol Renal Physiol 311:F1135-F1139 |
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