Characterization of the Nuclear Factor (Erythroid‐Derived 2)‐Like 2 (NRF2) Response in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Authors: Lutsic Jared , Tug Ali , Adrian Alexis , Torres Vicente , Irazabal Maria V. 
Published: April 2020

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development and enlargement of bilateral renal cysts, and the majority of renal complications including organ failure arise mainly as a consequence of the cystic burden along with associated inflammation and fibrosis. Abnormal epithelial cell proliferation, along with the inability to maintain planar cell polarity, underlies cyst formation and enlargement. Therefore, processes that stimulate renal cell proliferation have the potential to generate the cystic phenotype. Interestingly, an increased nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) response has been shown to direct cancer cells into an anabolic mode that favors cellular proliferation, and has been associated with renal cyst formation in experimental and human fumarate hydratase deficiency. However, the Nrf2 response has not been described in ADPKD. We hypothesized that early ADPKD presents with an elevation in the Nrf2 response that favors cellular proliferation and contributes to cystogenesis.

Methods

We sought to longitudinally characterize the Nrf2 response and association with cystogenesis and fibrosis in a slow progressive mouse model of ADPKD (Pkd1RC/RC) and its wildtype controls (n=6 males, 6 females per group). Urine and plasma samples were collected at 30, 60, 120, and 180 days for chemistries and metabolic profiles, and cystic index (CI), and total kidney volume (TKV) were determined from abdominal MRI. Nrf2 levels and related response enzymes, as well as cell proliferation and fibrosis were analyzed using western‐blots, immunofluorescence, and assay kits.

Results

At 30 days, Pkd1RC/RC mice presented increased CI (Figure
1A) and TKV/BW. However, serum creatinine and fibrotic markers were not different compared to controls. Pkd1RC/RC mice exhibited elevated Nrf2 expression and immunoreactivity early on that declined as ADPKD progressed from 30 to 180 days (Figure
1B) and correlated directly with cell proliferation (R2=0.693, p<0.05) and inversely with fibrotic markers (R2=0.672, p<0.05).

Conclusions

Our study shows longitudinal changes in the Nrf2 response in Pkd1RC/RC mice that are associated with cystogenesis early on and renal fibrosis at later stages of the disease. These findings have significant implications for the treatment of human ADPKD, and suggest that Nrf2 modulators might represent an advantageous intervention for the disease

Support or Funding Information

NIDDK R21 DK118391, R25‐DK101405, NIDDK P30 DK090728

A) Representative H&E‐stained kidney mid‐sections from Wild Type (WT) and Pkd1 RC/RC mice at 1 month. Pkd1 RC/RC mice presented increased cystic index (CI) from early stages of the disease. CI is calculated as % of cyst area within the total kidney section. B) Longitudinal levels of Nrf2 activation in WT and Pkd1 RC/RC mice. Pkd1 RC/RC mice exhibited elevated Nrf2 levels early on that declined as the disease progressed. Nrf2 activation is calculated from nuclear extracts by colorimetric assay.

Figure 1