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Abstract: SA-PO474

Defective Glomerulotubular Balance (GTB) in PKD2 Mutant and Conditional PKD2 Knockout Mice Before Renal Cyst Formation

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Du, Zhaopeng, Yale University, New Haven, Connecticut, United States
  • Tian, Xin, Yale University, New Haven, Connecticut, United States
  • Ma, Ming, Yale University, New Haven, Connecticut, United States
  • Weinstein, Alan Mark, Weill Medical College of Cornell University, New York, New York, United States
  • Somlo, Stefan, Yale University, New Haven, Connecticut, United States
  • Wang, Tong, Yale University, New Haven, Connecticut, United States
Background

PC2 (Pkd2) is a nonselective calcium permeable cation channel belonging to the TRP channel family, at the cilia and ER, and functions as a Ca2+ channel in the ER. Previous studies showed Pkd2 mutation or knockout resulted in an absence of IP3 receptor mediated calcium release from the ER. We have reported that blocking IP3 receptor abolished the flow-modulation of Na+ and HCO3- transport in mouse proximal tubules. We investigated whether Pkd2 has a physiological function in response to flow-mediated PT transport.

Methods

The flow-mediated Na+ and HCO3- transport were studied by microperfusion of proximal tubules in vitro in WT, Pkd2+/-and Pkd2 conditional KO (Pkd2fx/fl;Pax8-rtTA;Tet-O-Cre) mice. The KO mice were induced with doxycycline from 4-6 and used 3-4 weeks after the end of induction (9-10 week old mice), before renal cysts have formed. Proximal tubules were perfused in vitroat low (5 nl/min) and high (20 nl/min) perfusion rates, and the fluid (Jv) and HCO3- (JHCO3) absorption were measured by the changes of 3H-Inulin and total CO2 in the original and collected fluid. JNa was estimated from the change of Jv and the assumption of isotonic transport.

Results

When perfusion was increased from 5 to 20 nl/min, Jv and JNa increased 48% and JHCO3 doubled in WT. In contrast, the flow-stimulated component of Jv and JNa could not be detected, and that of JHCO3 was significantly reduced in both Pkd2+/- and the Pkd2-/- mice, similar to the effect of the IP3 receptor antagonist (2-APB).

Conclusion

These results indicate that Pkd2 is necessary for normal flow-mediated PT transport, and support the hypothesis that impaired GTB may contribute to renal cyst formation.

Effect of Axial Flow on Sodium and Bicarbonate Absorption in PTs of WT and Pkd2 Mutant Mice
 nJv (nl/min/mm)JNa(pmole/min/mm)JHCO3 (pmole/min/mm)
Flow rates 5nl/min │ 20nl/min5nl/min │ 20nl/min5nl/min │ 20nl/min
WT130.95±0.1 │ 1.44±0.1*134.2±5 │ 197.8±6*70.8±4 │ 138.7±5*
Pkd2+/-110.74±0.1† │ 0.67±0.1†108.9±11 │ 98.8±7†68.6±6 │ 87.9±4†
Pkd2-/-70.64±0.1† │ 0.89±0.2†94.5±12 │130.2±23†60.8±7 │ 76.9±5†

* P< 0.05 compared from low flow rate; †P<0.05 compared with WT control at the same flow rate.

Funding

  • NIDDK Support