Temporally‐Induced Nephron Polycystin‐1 Knockout Causes Salt and Water Wasting and Reduced Blood Pressure in the Absence of Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is characterized by the early onset of hypertension that does not strictly correlate with cyst formation. Since deficiency of polycystin‐1 is the major cause of PKD, it may be that polycystin‐1 is directly involved in regulation of renal salt excretion and blood pressure regulation, i.e., it may exert physiological effects on kidney function independent of its involvement in cystogenesis. One previous study showed that distal nephron PC‐1 knockout caused fluid and electrolyte wasting, however these mice had dilated tubules, increased kidney size and increased renal cell proliferation, hence renal injury may have confounded findings. To address this, we administered doxycycline to Pax8‐rtTA/tetO7‐CMV*‐Cre/homozygous floxed Pkd1 mice at 3 months of age and studied the mice over the next 2–3 months. These mice demonstrated nephron‐specific Pkd1gene targeting. No cysts or tubule dilation were evident in any of the KO kidneys for at least 3 months after doxycycline administration. Food and water intake were similar between control (no doxycycline) and KO mice (same genotype as controls + doxycycline) on a normal, low and high Na+ intake (5–7 days each diet). Urine volume, urinary K+ excretion and urinary Na+ excretion were higher in KO vs. control mice during the first 2 days of high salt intake. Systolic and diastolic blood pressure were lower (by 4–5 mmHg) in KO mice during all diets. Plasma renin concentration was similar between control and KO mice on a normal Na+ diet and fell to the same degree in both genotypes on a high Na diet. Urinary endothelin‐1 and urinary nitrite/nitrate excretion were similar between control and KO mice on a normal Na+ diet and increased to the same degree in both genotypes on a high Na+ diet. KO mice had more rapid Na+ and K+ excretion following an acute intraperitoneal NaCl load and excreted more Na+ and K+ over the 7 hr following salt loading. Taken together, these data suggest that polycystin‐1 is involved in regulating renal electrolyte excretion in the absence of renal pathology. Surprisingly, nephron polycystin‐1 may exert a net Na+ and K+ retaining effect. Functional polycystin‐1 disruption in PKD does not appear to explain, independent of cyst formation, the hypertension observed early in the course of PKD.Support or Funding InformationNIH P01 HL136267This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.