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Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation.

ABSTRACT: Kallistatin is an inhibitor of tissue kallikrein and also inhibits the Wnt pathway. Its role in diabetic nephropathy (DN) is uncertain. Here we reported that serum kallistatin levels were significantly increased in diabetic patients with DN compared to those in diabetic patients without DN and healthy controls, and positively correlated with urinary albumin excretion. In addition, renal kallistatin levels were significantly upregulated in mouse models of type 1 (Akita, OVE26) and type 2 diabetes (db/db). To unveil the effects of kallistatin on DN and its underlying mechanism, we crossed transgenic mice overexpressing kallistatin with OVE26 mice (KS-tg/OVE). Kallistatin overexpression exacerbated albuminuria, renal fibrosis, inflammation, and oxidative stress in diabetes. Kallikrein activity was inhibited while the renin-angiotensin system (RAS) upregulated in the kidney of KS-tg/OVE mice compared to WT/OVE mice, suggesting a disturbed balance between the RAS and kallikrein-kinin systems. As shown by immunostaining of endothelial makers, renal vascular densities were decreased accompanied by increased HIF-1α and erythropoietin levels in the kidneys of KS-tg/OVE mice. Taken together, high levels of kallistatin exacerbate DN at least partly by inducing RAS overactivation and hypoxia. The present study demonstrated a positive correlation between kallistatin levels and DN, suggesting a potential biomarker for prognosis of DN.

SUBMITTER: Yang Y

PROVIDER: S-EPMC7302980 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation.

Yang Yanhui Y He Xuemin X Cheng Rui R Chen Qian Q Shan Chunyan C Chen Liming L Ma Jian-Xing JX

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200430 6

Kallistatin is an inhibitor of tissue kallikrein and also inhibits the Wnt pathway. Its role in diabetic nephropathy (DN) is uncertain. Here we reported that serum kallistatin levels were significantly increased in diabetic patients with DN compared to those in diabetic patients without DN and healthy controls, and positively correlated with urinary albumin excretion. In addition, renal kallistatin levels were significantly upregulated in mouse models of type 1 (Akita, OVE26) and type 2 diabetes ...[more]

PMID: 32352602

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Project description:BackgroundDiabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss of TIMP3, an Extracellular Matrix bound protein affecting both inflammation and fibrosis, is a hallmark of DN in human subjects and mouse models.MethodsThis study was designed to provide evidences that the modulation of the system involving TIMP3 and its target A Disintegrin And Metalloproteinase 17 (ADAM17), may rescue kidney pathology in diabetic mice. Mice with cell-targeted overexpression of TIMP3 in myeloid cells (MacT3), podocyte-specific ADAM17 knockout mice (∆PodA17), and DBA/2J mice, were rendered diabetic at 8 weeks of age with a low-dose streptozotocin protocol. DBA/2J mice were administered new peptides based on the human TIMP3 N-terminal domain, specifically conjugated with G3C12, a carrier peptide highly selective and efficient for transport to the kidney. Twelve weeks after Streptozotocin injections, 24-hour albuminuria was determined by ELISA, kidney morphometry was analyzed by periodic acid-shift staining, and Real Time-PCR and western blot analysis were performed on mRNA and protein extracted from kidney cortex.ResultsOur results showed that both genetic modifications and peptides treatment positively affect renal function and structure in diabetic mice, as indicated by a significant and consistent decline in albuminuria along with reduction in glomerular lesions, as indicated by reduced mesangial expansion and glomerular hypertrophy, decreased deposition of extracellular matrix in the mesangium, diminished protein expression of the NADPH oxidases 4 (NOX4), and the improvement of podocyte structural markers such as WT1, nephrin, and podocin. Moreover, the positive effects were exerted through a mechanism independent from glycemic control.ConclusionsIn diabetic mice the targeting of TIMP3 system improved kidney structure and function, representing a valid approach to develop new avenues to treat this severe complication of diabetes.

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Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation.

Publications

Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation.

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