Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats

Abstract

BackgroundStudies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus.MethodsOLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7–25 weeks.ResultsOLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters.ConclusionsThis study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.

A case of secondary focal segmental glomerulosclerosis associated with malignant hypertension

“…Molecular pathogenesis, i.e., activation of the reninangiotensin-aldosterone system, may play a role in the damage associated with hyperfiltration injury [26][27][28]. Malignant hypertension is usually accompanied by a high secretion of renin by the kidney, which is not downregulated by the rise in blood pressure.…”

“…Angiotensin II contributes to systemic hypertension by constricting the efferent arterioles, causing an increase in intraglomerular pressure and filtration fraction. In addition, angiotensin II also acts directly on the endothelial cells as well as podocyte injury to result in the development of glomerular disease [26][27][28]. Indeed, in a rat model, angiotensin II-dependent hypertension exhibits endothelial cells and podocyte injury as well as secondary FSGS [11].…”

Automated image analysis of a glomerular injury marker desmin in spontaneously diabetic Torii rats treated with losartan

“…Detailed methods are available in the Supplementary Materials and Methods, see section on supplementary data given at the end of this article. For analysis of superficial and juxtamedullary glomeruli, glomeruli located within a fixed distance from kidney surface were defined as superficial glomeruli, as described previously (Sofue et al 2012). The remaining glomeruli located at the inner renal regions were classified as juxtamedullary glomeruli.…”

“…Increased desmin immunostaining in glomerular podocytes has been widely utilized as a sensitive podocyte injury marker and observed in various rat models of glomerular disease, including Heymann nephritis, and puromycin aminonucleoside (PAN)-induced nephrotoxicity, as well as diabetic nephropathy, such as Zucker diabetic fatty rats and Otsuka Long-Evans Tokushima fatty (OLETF) rats (Floege et al 1992, Hoshi et al 2002, Herrmann et al 2012, Sofue et al 2012. Accordingly, the quantification of glomerular desmin as a podocyte injury marker would be quite important for quantitatively evaluating early glomerular disease, particularly in the field of preclinical drug efficacy studies as well as for the elucidation of the pathophysiology of diabetic nephropathy.…”

“…Considering the heterogeneity of glomerular injuries in renal cortex (Sofue et al 2012), the limited number of glomeruli analyzed by hand could lead to arbitrary selection and improper results. Automatic segregation of glomeruli from other renal structures is quite challenging for most image analysis software, which mostly depend on color feature information for recognition of tissue structures, because the colors of glomeruli are similar to those of other renal structures.…”