Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease.

Shannon Mcleland,Katharine Lunn,Rene Paschall,David Maranon,Ann Hess,Jack Lawson,Rachel Cianciolo,Andrea Erickson,Jessica Quimby,Susan Bailey,Jonathan Elliott

doi:10.3390/vetsci8120314

Abstract

Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.

Highlights

Chronic kidney disease (CKD) is a common naturally-occurring disease in cats that increases in prevalence with age [1,2]
Percent global glomerulosclerosis and cortical and corticomedullary inflammatory infiltrate and fibrosis scores were significantly higher in chronic kidney disease (CKD) cats than in adult and senior cats
Our results suggest that p16 is a mediator of renal senescence in both senior cats and cats with CKD, as cats with CKD exhibited accelerated p16-mediated senescence in both the cortex and corticomedullary junction of the kidney, beyond what would be expected for normal aging

Summary

Introduction

Chronic kidney disease (CKD) is a common naturally-occurring disease in cats that increases in prevalence with age [1,2]. The most frequent morphologic diagnosis in cats with CKD is tubular degeneration and atrophy with interstitial inflammation, fibrosis, and glomerulosclerosis, which increase in severity with the progression of disease stages [3]. Studies to better understand its pathophysiology and identify prospective target for therapeutic intervention are needed. Insights into this heterogeneous population of patients with naturally-occurring disease have translational potential for aging human kidney disease patients due to similarities in histopathologic lesions despite some differences in clinical characteristics [6,7,8,9]

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