title: HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II.
abstract: Apoptosis is a driving force of diabetic end-organ damage, including diabetic nephropathy (DN). However, the mechanisms that modulate diabetes-induced cell death are not fully understood. Heat shock protein 27 (HSP27/HSPB1) is a cell stress protein that regulates apoptosis in extrarenal cells and is expressed by podocytes exposed to toxins causing nephrotic syndrome. We investigated the regulation of HSPB1 expression and its function in podocytes exposed to factors contributing to DN, such as high glucose and angiotensin (Ang) II. HSPB1 expression was assessed in renal biopsies from patients with DN, minimal change disease or focal segmental glomerulosclerosis (FSGS), in a rat model of diabetes induced by streptozotocin (STZ) and in Ang II-infused rats. The regulation of HSPB1 was studied in cultured human podocytes and the function of HSPB1 expressed in response to pathophysiologically relevant stimuli was explored by short interfering RNA knockdown. Total kidney HSPB1 mRNA and protein expression was increased in rats with STZ-induced diabetes and in rats infused with Ang II. Upregulation of HSPB1 protein was confirmed in isolated diabetic glomeruli. Immunohistochemistry showed increased glomerular expression of HSPB1 in both models and localized glomerular HSPB1 to podocytes. HSPB1 protein was increased in glomerular podocytes from patients with DN or FSGS. In cultured human podocytes HSPB1 mRNA and protein expression was upregulated by high glucose concentrations and Ang II. High glucose, but not Ang II, promoted podocyte apoptosis. HSPB1 short interfering RNA (siRNA) targeting increased apoptosis in a high-glucose milieu and sensitized to Ang II or TGFβ1-induced apoptosis by promoting caspase activation. In conclusion, both high glucose and Ang II contribute to HSPB1 upregulation. HSPB1 upregulation allows podocytes to better withstand an adverse high-glucose or Ang II-rich environment, such as can be found in DN.
authors.affiliation: Nefrología, IIS-Fundación Jiménez Diaz, Madrid, Spain.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.forename: Elsa
authors.initials: E
authors.lastname: Sanchez-Lopez
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito-Martin
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000222:Adaptation, Physiological; D000293:Adolescent; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003928:Diabetic Nephropathies / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis / Q000502:physiology*; D006360:Heat-Shock Proteins; D006801:Humans; D008875:Middle Aged; D018832:Molecular Chaperones; D050199:Podocytes / Q000502:physiology*; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D000804:Angiotensin II; D020169:Caspases; D005947:Glucose