Increase in tubular flow directly induces hypertrophy of proximal tubular cells

Glomerular hyperfiltration, as seen for instance in diabetic nephropathy or in response to loss of kidney tissue, induces hypertrophy of proximal tubular cells. In our study we tested whether the increase in proximal tubular flow which results from glomerular hyperfiltration can directly induce hypertrophy of proximal tubular cells. Unilateral nephrectomy in mice resulted in an increase in the GFR (130% of control) and in an increase in the cell area of proximal tubular cells in kidney sections (117% of sham controls) within 3 days, indicating functional and structural adaptation to loss of kidney tissue is a rapid process. The flow velocity in proximal tubules of living mice was around 400 µm/s as determined by intravital microscopy. Accordingly, murine primary proximal tubular cells (PPTC) or LLCPK1 cells were superfused for 20 hours in closed perfusion chambers with serum‐ and hormone‐free medium at flow velocities between 0 and 1mm/s resulting in physiological shear stress rates. In fact, higher flow velocities induced hypertrophy of PPTC and LLCPK1. For instance, cells that had been perfused at 500 µm/s had higher protein/DNA ratio (+25%), as a marker for hypertrophy, compared to cells perfused at 250 µm/s. In parallel, cell area (morphometry of cells directly in perfusion chamber, +20%) and cell volume (isolated cells, electric field cell counting; CASY, +15%) were significantly higher at 500 compared with 250 µm/s. The flow dependent hypertrophy only occurred within the physiological flow range, since higher flow rates resulted in reduced cell viability and cell size. Increase in tubular flow and sheer stress within the physiological range can directly induce hypertrophy of proximal tubular cells independent of changes in neurohumoral stimulation.