| dc.description.abstract | Chronic kidney disease (CKD) represents a massive unmet clinical need, as there are virtually no pharmaceutical options for treatment of renal injury. A recent study identified cadherin-11 (CDH11) as a potential biomarker for CKD. CDH11 is present in kidney biopsies and urine samples of CKD patients, and its expression is increased in CKD mouse models. We have investigated the role of CDH11 as both a mediator and therapeutic target of CKD. In this work, we used three mouse models of CKD to evaluate the role of CDH11: aristolochic acid nephropathy (AAN), unilateral ureteral obstruction (UUO), and uninephrectomy/angiotensin II administration (Unx/AngII). In each of these models, we inhibited CDH11 genetically using transgenic mice and pharmacologically with the administration of a functional blocking antibody to CDH11. We also used de-identified electronic medical records to verify the clinical relevance of the proposed mechanism whereby CDH11 knockout improves kidney injury. We found that in mouse kidneys, CDH11 is exclusively expressed in injured proximal tubules (PTs). PTs play a critical role in CKD, as they are both a target and mediator of chronic injury. In models of CKD, both genetic and pharmacologic CDH11 inhibition improves renal function (BUN and proteinuria), diminishes cytokine production (TGF-β1 and IL-6 expression), and reduces tubular injury (KIM-1 and histological analysis). RNAseq from AAN- and Unx/AngII-injured kidneys revealed that CDH11 knockout mice had significantly increased expression of alpha-1 antitrypsin (AAT) compared to wild type controls. The protease inhibitor AAT has been shown to promote PT survival in several kidney injury models. Additionally, siRNA knockdown of CDH11 in immortalized PT cells in vitro results in elevated expression of AAT, confirming this mechanistic link. Using Cox proportional hazards models, we discovered that patients with AAT mutations have increased incidence of CKD on a per-allele basis, with hazard ratios as high as 5.35. These results identify CDH11 inhibition as a novel means of improving outcomes in murine CKD models and suggest an underlying mechanism of increased AAT expression and enhanced PT survival. These findings advance our understanding of CKD and outline a potential new therapeutic strategy. | |
