calpain and Renal-Insufficiency--Chronic

Podocytes have become a crucial target for interventions in proteinuric kidney diseases. Many studies have reported that overexpression of transient receptor potential cation channel protein 6 (TRPC6) in podocyte injury upregulates intracellular Ca. We investigated the involvement of tetrandrine in Ca. Tetrandrine decreased intracellular Ca. Tetrandrine has therapeutic potential in podocyte damage by blocking Ca

Topics: Animals; Benzylisoquinolines; Calcium; Calcium Channel Blockers; Calpain; Cell Line; Disease Models, Animal; Doxorubicin; Male; Mice; Podocytes; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Signal Transduction

A non‑classical calpain, calpain 6 (CAPN6), can inhibit skeletal muscle differentiation and regeneration. In the present study, the role of CAPN6 in the regulation of the autophagy of myoblasts

Topics: Animals; Apoptosis; Autophagy; Calpain; Cell Differentiation; Cytokines; Disease Models, Animal; Humans; Inflammation; Male; Microtubules; Muscle Development; Muscle, Skeletal; Muscular Atrophy; Myoblasts; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Signal Transduction

Evidence for reduced expression of cyclin G associated kinase (GAK) in glomeruli of patients with chronic kidney disease was observed in the Nephroseq human database, and GAK was found to be associated with the decline in kidney function. To examine the role of GAK, a protein that functions to uncoat clathrin during endocytosis, we generated podocyte-specific Gak-knockout mice (Gak-KO), which developed progressive proteinuria and kidney failure with global glomerulosclerosis. We isolated glomeruli from the mice carrying the mutation to perform messenger RNA profiling and unearthed evidence for dysregulated podocyte calpain protease activity as an important contributor to progressive podocyte damage. Treatment with calpain inhibitor III specifically inhibited calpain-1/-2 activities, mitigated the degree of proteinuria and glomerulosclerosis, and led to a striking increase in survival in the Gak-KO mice. Podocyte-specific deletion of Capns1, essential for calpain-1 and calpain-2 activities, also improved proteinuria and glomerulosclerosis in Gak-KO mice. Increased podocyte calpain activity-mediated proteolysis of IκBα resulted in increased NF-κB p65-induced expression of growth arrest and DNA-damage-inducible 45 beta in the Gak-KO mice. Our results suggest that loss of podocyte-associated Gak induces glomerular injury secondary to calcium dysregulation and aberrant calpain activation, which when inhibited, can provide a protective role.

Topics: Animals; Calpain; Diabetic Nephropathies; Female; Glomerulosclerosis, Focal Segmental; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Podocytes; Protein Serine-Threonine Kinases; Renal Insufficiency, Chronic

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.

Topics: Aging; Animals; Calpain; Drug Evaluation, Preclinical; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Klotho Proteins; Male; Mice, Knockout; Phenotype; Renal Insufficiency, Chronic; Sulfonamides; Vascular Calcification