title: Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes.
abstract: Growth differentiation factor 15 (GDF15) is emerging as valuable biomarker in cardiovascular disease and diabetic kidney disease. Also, GDF15 represents an early response gene induced after tissue injury and studies performed in GDF15 knockout (KO) mice suggest that GDF15 plays a protective role after injury. In the current study, we investigated the role of GDF15 in the development of diabetic kidney damage in type 1 and type 2 models of diabetes. Renal damage was assessed in GDF15 KO mice and wild-type (WT) mice in streptozotocin type 1 and db/db type 2 diabetic models. Genetic deletion of GDF15 augmented tubular and interstitial damage in both models of diabetes, despite similar diabetic states in KO and WT mice. Increased tubular damage in KO animals was associated with increased glucosuria and polyuria in both type 1 and type 2 models of diabetes. In both models of diabetes, KO mice showed increased interstitial damage as indicated by increased α-smooth muscle actin staining and collagen type 1 expression. In contrast, glomerular damage was similarly elevated in diabetic KO and WT mice. In type 1 diabetes, GDF15 KO mice demonstrated increased expression of inflammatory markers. In type 2 diabetes, elevated levels of plasma creatinine indicated impaired kidney function in KO mice. GDF15 protects the renal interstitium and tubular compartment in experimental type 1 and 2 diabetes without affecting glomerular damage.
authors.affiliation: Dept. Clinical Pharmacology, UMCG, A. Deusinglaan 1, 9713AV Groningen, The Netherlands. l.e.deelman@umcg.nl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mazagova
authors.forename: Hendrik
authors.initials: H
authors.lastname: Buikema
authors.forename: Azuwerus
authors.initials: A
authors.lastname: van Buiten
authors.forename: Marry
authors.initials: M
authors.lastname: Duin
authors.forename: Maaike
authors.initials: M
authors.lastname: Goris
authors.forename: Maria
authors.initials: M
authors.lastname: Sandovici
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.forename: Leo E
authors.initials: LE
authors.lastname: Deelman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: C526141:Gdf15 protein, mouse; C526142:Gdf15 protein, rat; D055436:Growth Differentiation Factor 15
keywords: GDF15; TGF-β; diabetes