Aberrant Activation of Renal Functional Reserve and Reduced Tubule Flow, but Not Obstruction, is Associated with Cystogenesis in Pkd2 Mutant Kidneys

Disruption of PKD2 function causes polycystic kidney disease (PKD) and leads to the formation of cysts in the kidney in both mice and humans. PKD is progressive, initiating with the formation of tubule dilations that expand into large cysts, causing the destruction of renal parenchyma and loss of kidney function. The mechanisms initiating tubule dilation and expansion are uncertain. Tubule obstruction has been proposed as a factor contributing to cystogenesis. Here, we utilize a proximal tubule fluorescent dextran uptake assay to evaluate changes in tubule flow that occur during cyst initiation or expansion and functional decline. We did not observe overt signs of tubule obstruction during cyst initiation or expansion, even in larger cysts; however, the rate of tubule flow within individual nephrons was greatly diminished in cystic kidneys. Surprisingly, along with reduced tubule flow rate, we observe an increase in newly labeled dextran cells associated with disease in the Pkd2 mutants. These cells are spatially distinct from those absorbing the initial dextran and are detected in both cortical and medullary regions of mutant kidneys. Marker analysis indicated that the dextran+ medullary cells were in the loop of Henle and interstitial macrophages. These cells are not present in wild-type controls. This may be due to tubule or vasculature leakage and utilization of renal reserve capacity in mutants that become exhausted, associated with declining glomerular filtration rate (GFR) as cysts expand.