Disease relevance of Rapgef5

• Such responsiveness may contribute to reduced RBF and GFR during endotoxemia [1].
• Whether maintained renal vascular reactivity to vasoconstrictors contributes to the decrease in renal blood flow (RBF) and GFR observed during LPS-induced sepsis was tested by assessment of the acute effects of pressor agents on mean arterial pressure (MAP) and renal hemodynamics in endotoxemic and control mice [1].
• There were no significant differences in final body weight, urine volume and osmolality, GFR, proteinuria, or plasma levels of protein and urea between these two groups [2].
• Sepsis-associated acute renal failure is characterized by decreased GFR and tubular dysfunction [3].
• Eventually, with disease progression, compensating hemodynamic and structural factors fail to maintain GFR within normal limits [4].

High impact information on Rapgef5

• In the kidney it mediates the vascular response elicited by changes in NaCl concentration in the macula densa region of the nephron, thereby serving as an important regulator of GFR [5].
• The Gfr alpha3-/- mice exhibited severe defects in the superior cervical ganglion (SCG), whereas other ganglia appeared normal [6].
• GFR alpha2-expressing cells in the trigeminal and dorsal root ganglia are also depleted in NTN-/- mice [7].
• Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptor [8].
• These results suggest that while stringent physiologic pairing exists between GFR alpha1 and GDNF in renal and enteric nervous system development, significant cross-talk between GDNF and other GFR alpha coreceptors must occur in other neuronal populations [9].

Chemical compound and disease context of Rapgef5

• Inadequate formation of angiotensin II (Ang II) results in hypotension, loss of fluid homeostasis, lack of urine concentration, and failure to regulate GFR through the tubuloglomerular feedback (TGF) mechanism [10].
• The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 +/- 18.0 vs. 44.5 +/- 16.2 mul/min, P < 0.05) and renal blood flow (0.86 +/- 0.08 vs. 0.59 +/- 0.05 ml/min, P < 0.05) [11].
• In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days [12].

Biological context of Rapgef5

• From day 6 through day 14, the MAP had increased (P < 0.01) in AngII400, accompanied by a significant reduction in GFR to 1.05 +/- 0.04 ml. min(-1). g(-1) (P < 0.01) and elevation of renal vascular resistance (RVR) (day 6 versus day 14, 15.3 +/- 0.6 versus 19.2 +/- 1.2 mmHg. ml(-1). min(-1). g(-1); P < 0.05) [13].
• Inulin and para-aminohippurate clearances were used to assess GFR and renal plasma flow (RPF) in three groups of male C57Bl/6 mice anesthetized with inactin (100 mg/kg, intraperitoneally) and ketamine (10 mg/kg) [14].
• In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR [15].
• In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 +/- 6.6 vs. 50.2 +/- 6.6 mul/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip) [11].
• In contrast, mice treated with i.v. carboplatin or p.o. ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range [12].

Anatomical context of Rapgef5

• GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys [9].
• Midbrain dopaminergic and motor neurons in GFR alpha1 null mice were normal [9].
• Our data are the first to indicate a transduction-function role for GFR alpha2/neurturin signalling in a specific class of sensory neurons [16].
• Whole kidney GFR and single nephron GFR (SNGFR) have been reported to decrease after nitric oxide synthase (NOS) inhibition [17].

Associations of Rapgef5 with chemical compounds

• L-NAME reduced GFR in AT(2) -/- to 0.87 +/- 0.07 ml/min per g of kidney wt [18].
• The fall in GFR appears to be hemodynamically mediated by thromboxane A2 [4].
• The data indicate that nNOS in MD tonically attenuates the GFR-lowering influence of ambient luminal NaCl, which may serve to increase the fluid and electrolyte load to the distal tubule, consistent with a role of MD nNOS in tubuloglomerular feedback resetting [19].
• Among the vasoconstrictor challenges, only NE ameliorated the decrease in GFR 14 h after LPS injection [1].
• Even more remarkable, eNOS(-/-) C57BLKS db/db exhibited decreases in GFR to levels <50% of that in eNOS(+/+) C57BLKS db/db, as confirmed by increased serum creatinine [20].

Analytical, diagnostic and therapeutic context of Rapgef5

• To investigate the usage of these coreceptors for GDNF signaling in vivo, gene targeting was used to produce mice lacking the GFR alpha1 coreceptor [9].
• When studied at day 6, the MAP of AngII400 rats was not elevated (88 +/- 2 mmHg; NS versus vehicle), yet the GFR was higher (1.05 +/- 0.05 versus 1.25 +/- 0.05 ml. min(-1). g(-1); P < 0.05) accompanied by an increase in the filtration fraction (FF) (28.8 +/- 1.2 versus 37.2 +/- 0.8%; P < 0.001) [13].
• MAP in the control group was 77 +/- 2 mmHg; volume expansion alone did not change MAP significantly (83 +/- 2 mmHg), but led to significantly greater values in both GFR and RPF (1.35 +/- 0.14 versus 1.01 +/- 0.1 ml/min x g and 11.26 +/- 1.39 versus 6.29 +/- 0.5 ml/min x g, respectively) [14].
• Parathyroid hormone increased significantly 3 days after nephrectomy and peaked at 2 wk, despite reduction in GFR of < 50% [21].
• Using free-flow micropuncture techniques, the proximal-distal single-nephron GFR difference was found to be augmented in aquaporin-1 and Na/H exchanger-3 knockout mice, suggesting TGF activation in these strains of mice [22].

References