Torres, Vicente E.

The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.

Background Autosomal Dominant Polycystic Kidney Disease (PKD) is the most frequent hereditary renal disease and the fourth leading cause of end‐stage renal disease. However, the exact mechanisms of cystogenesis and disease progression remain to be elucidated. Recent evidence suggests that a metabolic reprograming may underlie the dysregulation of several signaling pathways known to be affected in PKD. To identify the metabolic pathways associated with cystogenesis in the PKD kidney, we characterized the urinary, plasma, and tissue metabolome of PCK (a well established model of PKD) compared to Sprague‐Dawley (SD) wild‐type rats. Methods Male and female PCK and SD rats were treated with dDAVP (PCK‐D, n=16 or SD‐D, n=12) to aggravate the cystic phenotype and achieve animals with different degrees of disease severity for a given age, or saline solution (PCK‐S, n=16 or SD‐S, n=12) as controls. Total kidney volume (TKV) gold standard to assess disease severity, were measured by MRI, and urinary, plasma, and tissue metabolites by proton nuclear magnetic resonance, 1H‐NMR. Kidney metabolites identified from renal tissues collected at euthanasia were correlated with TKV. Mitochondrial structure was assessed by electron microscopy in proximal tubules (PT), medullary thick ascending limb (mTAL), distal tubules (DT), and collecting ducts (CD). Results Consistent with previously published data, administration of dDAVP significantly aggravated the disease in PCK rats (TKV) without inducing a cystic phenotype in SD rats (). Analysis of PCK and SD metabolomes by Partial least squares‐discriminant analysis (PLS‐DA) score plots showed a significant separation between the groups (). Integration of tissue, urine and plasma analysis revealed 5 metabolites (α‐ketoglutarate, fumarate, malate, citrate, and hippurate) consistently differentially expressed, among which 4 participate in the mitochondrial tricarboxylic acid (TCA) cycle (). Moreover, tissue TCA cycle metabolites correlated directly with TKV (). Mitochondrial area and matrix density were preserved in PT, mTAL, and DT of PCK rats, yet disruption of cristae membranes, swelling, and decreased matrix density were observed in their CD cystic cells (). Conclusions Comprehensive multilevel metabolomics analysis showed significant dysregulations of several mitochondrial TCA cycle metabolites in PCK rats, which further aggravated with the more severe phenotype. Notably, these changes were associated with mitochondrial structural abnormalities in the CD. Our observations suggest that mitochondrial damage and metabolic dysregulations may be implicated in cystogenesis, and position mitochondria as important therapeutic targets in PKD. Support or Funding Information This study was supported by the Mayo Translational Polycystic Kidney Disease Center (NIDDK P30 DK090728) and an endowment from Robert M. and Billie J. Pirnie for Kidney Research

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups. Methods This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46–56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD). Results Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly. Conclusion Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.