The overall efficacy of kidney function requires the close coordination of glomerular filtration and tubular reabsorption. This coordination is mediated by the combined processes of glomerulo-tubular balance (GTB), the flow dependence of tubular reabsorption, and tubuloglomerular feedback (TGF),the negative feedback regulation of nephron filtration rate (SNGFR) by late proximal tubular flow rate (VLP) mediated by the macula densa juxtaglomerular apparatus. GTB and TGF act in combination to constitute a """"""""TGF system."""""""" Increases in VLP and increased NaCl delivery to the macula densa (MD) leads to TGF activation. TGF activation leads to loss of homeostatic efficiency (C) of TGF, as evaluated by online videometric flow velocitometric (VMFV) techniques. We have observed restoration of C within 30- 40 minutes and an increase in renal blood flow, an index of TGF resetting or temporal adaptation. When TGF is activated by benzolamide, over 24 hours and then discontinued, we find complete temporal adaptation of TGF with a rightward shift in the profile relating VLP to SNGFR and GFR/SNGFR hyperfiltration. Temporal adaptation of TGF was associated with increased bNOS expression in the MD and prevented by bNOS inhibitors. We will utilize renal microperfusion, glomerular hemodynamics, VMFV, measurements of distal tubular MD signal with ionic conductivity electrodes, measurements of renal O2 consumption and PO2 by microelectrode, enzymatic, HPLC, molecular and cellular biologic and immunocytochemical techniques to examine the mechanistic basis of TGF temporal adaptation.
Specific Aim number 1. We will examine the mechanistic basis of TGF temporal adaptation to reductions in APR and increased systemic blood pressure in early and later temporal phases. Temporal adaptations of TGF to reductions in flow to the MD will also be examined using closed loop and open loop mode assessments.
Specific Aim number 2. bNOS activity and protein expression is a necessary requirement for temporal TGF adaptation. We will examine contributions to bNOS in terms of COX-2 activity and changes in intrarenal renin- angiotensin system. The roles of kidney O2 consumption and PO2, bradykinin, kidney NMDA receptor and arginine reabsorption and arginine metabolites will also be assessed.
Specific Aim number 3. Nephrotoxic acute renal failure (uranyl nitrate) represents a failure of TGF to adapt temporally and no increase in bNOS, possibly due to altered O2 consumption, impaired L-arginine uptake or iNOS induced autoinhibition of bNOS. The mechanisms contributing to temporal adaptation of TGF after contralateral nephrectomy will also be examined.
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