Polycystic kidney diseases (PKDs) are lethal, hereditary disorders characterized by hyperplasia of the renal epithelium, cyst formation and massive kidney enlargement. Our laboratory discovered that agonists that increase intracellular cAMP, such as arginine vasopressin (anti-diuretic hormone), catecholamines and prostaglandins, accelerate the proliferation of cyst epithelial cells. Stimulation of protein kinase A by cAMP activates the extracellular signal-regulated kinase1/2 (ERK) pathway and cell proliferation in PKD, but inhibits ERK and proliferation of normal human kidney cells. Recent findings suggest that mutations in gene products of most hereditary cystic disorders cause abnormal calcium metabolism in renal tubule cells. We are investigating the central hypothesis that in human PKD dysfunctional calcium metabolism uncovers a common cellular pathway leading to cAMP-dependent activation of B-Raf, a key kinase in ERK activation and cell proliferation. Understanding these fundamental mechanisms for hyperplasia of cystic epithelia will hasten the development of therapies to slow the progression of PKD in patients.
Over the past several years, my laboratory has been investigating the role of the collecting duct system in urine formation. The mammalian kidneys regulate salt and water excretion with extraordinary precision, balancing urinary excretion to salt and water intake. Despite the clinical importance, there is incomplete understanding of how the kidney precisely controls salt balance around a net urinary NaCl excretion equal to 0.5 to 1 % of the filtered load. The classical view of salt and water regulation focuses on mechanisms that control renal blood flow, glomerular filtration and salt absorption. It is well established that the collecting ducts reabsorb vast quantities of salt and water. We discovered, unexpectedly, that collecting ducts have an intrinsic capacity for salt and fluid secretion, thus harboring a counteractive force to NaCl absorption. cAMP plays a central role in controlling net transport by activating transepithelial Cl- secretion. Ammonium which is normally found in relatively high concentrations within the interstitial fluid of the renal inner medulla amplifies cAMP mediated anion and fluid secretion. We are investigating the hypothesis that inner medullary collecting ducts, the last nephron segments in contact with the tubular fluid, make final adjustments to the fluid before it is excreted as urine.