Date of Award
Joan C. Edwards School of Medicine
Type of Degree
Dr. Richard Egleton, Committee Chairperson
Dr. Oscar Carretero
Dr. Todd L. Green
Dr. Elsa I. Mangiarua
Dr. Travis Salisbury
Obesity is a public health problem and is associated with salt-sensitive hypertension, kidney inflammation and fibrosis. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a tetra-peptide with anti-inflammatory and anti-fibrotic properties but its effect on kidney damage in obesity is unknown. We hypothesized that high salt fed Zucker obese (ZO) rats develop renal damage, inflammation and fibrosis and that Ac-SDKP prevents these changes. Zucker lean (ZL) rats served as controls. Animals were treated with Ac-SDKP while maintained on either a normal-salt or HS diet for 8 weeks. Systolic blood pressure (SBP), albuminuria, renal inflammation and fibrosis were evaluated. HS diet increased macrophage infiltration in the kidneys of both ZL and ZO rats but was significantly higher in HS fed ZO rats. Ac-SDKP prevented macrophage infiltration in ZO rats. Similarly, glomerulosclerosis, cortical and medullary interstitial fibrosis were increased in ZO rats fed the HS diet, and Ac-SDKP attenuated these alterations. SBP was increased in HS-fed ZO rats, and was significantly decreased with Ac-SDKP treatment. AcSDKP treatment failed to improve albuminuria ZO rats. Conclusion: Ac-SDKP treatment in HSfed ZO rats prevented renal damage by reducing inflammation, fibrosis, and SBP. Additionally, we studied the renal hemodynamics in ZO rats. ZO rats have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by the afferent arteriole (Af-Art) resistance which in turn is regulated by two intrinsic feedback mechanisms, tubuloglomerular feedback (TGF) that causes Af-Art constriction and connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in sodium chloride (NaCl) transport in the connecting tubule via the epithelial sodium channel (ENaC). Since CTGF is a dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation and decreases PGC in ZO rats. We measured stop-flow pressure (PSF), surrogate of PGC in ZO rats using in-vivo renal micropuncture. Maximal TGF response was attenuated while CTGF was elevated in ZO rats compared to ZL rats. CTGF inhibition with ENaC normalized the maximum PSF change in ZO rats indicating an important role of CTGF in TGF attenuation. Conclusion: enhanced CTGF contributes to TGF attenuation in ZO rats and potentially contributes to progressive renal damage.
Obesity -- Complications -- Research.
Obesity -- Research.
Maheshwari, Mani, "Role of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) and renal hemodynamics on obesity related renal damage" (2018). Theses, Dissertations and Capstones. 1195.