Polycystin-1 dysfunction impairs electrolyte and water handling in a renal precystic mouse model for ADPKD

Abstract

The PKD1 gene encodes polycystin-1 (PC1), a mechanosensor triggering intracellular responses upon urinary flow sensing in kidney tubular cells. Mutations in PKD1 lead to autosomal dominant polycystic kidney disease (ADPKD). The involvement of PC1 in renal electrolyte handling remains unknown since renal electrolyte physiology in ADPKD patients has only been characterized in cystic ADPKD. We thus studied the renal electrolyte handling in inducible kidney-specific Pkd1 knockout (iKsp- Pkd1) mice manifesting a precystic phenotype. Serum and urinary electrolyte determinations indicated that iKsp- Pkd1 mice display reduced serum levels of magnesium (Mg), calcium (Ca), sodium (Na), and phosphate (P) compared with control ( Pkd1) mice and renal Mg, Ca, and P wasting. In agreement with these electrolyte disturbances, downregulation of key genes for electrolyte reabsorption in the thick ascending limb of Henle's loop (TA;, Cldn16, Kcnj1, and Slc12a1), distal convoluted tubule (DCT; Trpm6 and Slc12a3) and connecting tubule (CNT; Calb1, Slc8a1, and Atp2b4) was observed in kidneys of iKsp- Pkd1 mice compared with controls. Similarly, decreased renal gene expression of markers for TAL ( Umod) and DCT ( Pvalb) was observed in iKsp- Pkd1 mice. Conversely, mRNA expression levels in kidney of genes encoding solute and water transporters in the proximal tubule ( Abcg2 and Slc34a1) and collecting duct ( Aqp2, Scnn1a, and Scnn1b) remained comparable between control and iKsp- Pkd1 mice, although a water reabsorption defect was observed in iKsp- Pkd1 mice. In conclusion, our data indicate that PC1 is involved in renal Mg, Ca, and water handling and its dysfunction, resulting in a systemic electrolyte imbalance characterized by low serum electrolyte concentrations.

Tubular flow activates magnesium transport in the distal convoluted tubule

“…According to our findings, Mg 2+ reabsorption in DCT might be much lower in PKD than in normal physiologic conditions due to the absence of flow as a consequence of cyst formation. In an animal model of early PKD, Mg 2+ reabsorption was reduced (49). Contrarily, diuretics ( i.e ., furosemide, acetazolamide, or type 2 sodium‐glucose transporter inhibitors) increase the prourinary flow, resulting in an elevated FSS along the nephron (50, 51).…”

Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease

“…Inducible kidney‐specific Pkd1 knockout mice (iKsp‐ Pkd1 lox/lox ) were used to assess the role of PC1, in vivo, in urinary ATP excretion. Tamoxifen was administered, via oral gavage, to iKsp‐ Pkd1 lox/lox mice on postnatal days 18, 19, and 20 (PN18) to induce a kidney specific knockout of Pkd1 (iKsp‐ Pkd1 del ) . iKsp‐ Pkd1 lox/lox mice which received no tamoxifen were considered as age and genotype‐matched controls.…”

“…Precystic kidneys were extracted, weighed, and collected in liquid nitrogen and stored at −80°C for mRNA isolation. These samples were obtained from a previously performed study …”

Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2–Mediated Blood Pressure Reduction Independent of Cystogenesis

“…Studies addressing this issue have primarily analyzed cell lines or cells isolated from cystic kidneys, involve polycystic kidney disease models with mutation of genes other than Pkd1, and have yielded conflicting results. [4][5][6][7] In an attempt to address this issue, Verschuren et al 8 recently developed a tamoxifen-inducible distal nephron (Cre recombinase under control of the kidney-specific cadherin [Ksp] promoter) Pkd1 gene-targeted mouse. These mice were given tamoxifen at postnatal days 18-20 and studied on a normal salt diet at days 40 or 47 postnatal.…”