Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Abstract

Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10-to 12-wk-old male noncystic Pkd1 ϩ/Ϫ and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

Kidney Injury Accelerates Cystogenesis via Pathways Modulated by Heme Oxygenase and Complement

“…[10][11][12] Particularly attractive mediators of such effects are macrophages, a cell type essential for pathogenesis of both AKI 50 and ADPKD. 45 Specifically, in the Cys1 cpk model injury reduction (i.e., by HO induction) lowered macrophage activity, as reflected by decreased expression of genes encoding macrophage markers CD14 (Figure 1), macrophage activation marker CD32 (Fcgr2b) and an M2-marker Ccr5 (both by 40%; P=0.041 and P=0.025); reduction of other M2 markers (e.g., Arg1 by 28%, CD163 by 30%) did not reach statistical significance.…”

“…9 AKI reportedly accelerates renal cystogenesis in several other PKD models. [10][11][12] Although AKI is an important trigger for cystogenesis, it remains unknown whether milder chronic renal injury, such as that caused by PKD gene defects, also accelerates cystogenesis. The similarity of the renal injury responses during AKI and PKD gene defect-induced cyst formation, as reflected by genome-wide transcriptional analyses, 13,14 suggests a central role of PKD gene mutation-induced injury in renal cystogenesis.…”

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

“…The prevalence of cyst formation was higher-albeit still relatively rare-on a Pkd1 del,lox background, supporting the idea that haploinsufficiency of surrounding cells may enhance cyst formation and progression ( Figure 3B). 11,21 Thus, within a period of 6 months after scattered Pkd1 deletion, the adult kidney remains largely resistant to cyst formation, even after renal injury.…”

Autophagy and regulation of cilia function and assembly

“…82 PC1 and PC2 are critical for cellular repair and controlled growth, as well as for division of tubule cells after kidney injury, thus explaining the injury sensitivity of ADPKD kidneys. 83,84 ADPKD leads to kidney enlargement with increasing numbers and size of cysts over time because of abnormal renal epithelial cell growth, together with a disturbed fluid transport resulting in end-stage renal disease in 50% of patients.…”