Abstract
Glomerular hypertension and hyperfiltration in early diabetes are associated with development and progression of diabetic kidney disease. The tubular hypothesis of diabetic hyperfiltration proposes that it is initiated by a primary increase in sodium (Na) reabsorption in the proximal tubule (PT) and the resulting tubuloglomerular feedback (TGF) response and lowering of Bowman space pressure (P(Bow)). Here we utilized a mathematical model of the human kidney to investigate over acute and chronic timescales the mechanisms responsible for the magnitude of the hyperfiltration response. The model implicates that the primary hyperreabsorption of Na in the PT produces a Na imbalance that is only partially restored by the hyperfiltration induced by TGF and changes in P(Bow) Thus secondary adaptations are needed to restore Na balance. This may include neurohumoral transport regulation and/or pressure-natriuresis (i.e., the decrease in Na reabsorption in response to increased renal perfusion pressure). We explored the role of each tubular segment in contributing to this compensation and the consequences of impairment in tubular compensation. The simulations indicate that impaired secondary downregulation of transport potentiated the rise in glomerular hypertension and hyperfiltration needed to restore Na balance at a given level of primary PT hyperreabsorption. Therefore, we propose for the first time that both the extent of primary PT hyperreabsorption and the degree of impairment of the distal tubular responsiveness to regulatory signals determine the level of glomerular hypertension and hyperfiltration in the diabetic kidney, thereby extending the tubule-centric concept of diabetic hyperfiltration and potential therapeutic approaches beyond the proximal tubule.