Molecular analysis of human glomerular disease.

Abstract: The development of molecular techniques has added a significant new dimension to the study of experimental pathology and of cellular biology of the kidney. Since the field is relatively new and many methods lack the sensitivity required for small fragments of tissue, there is very little data on renal biopsies [1]. In addition, ethical considerations have limited the amount of tissue that can be devoted to experimental techniques. These have combined to slow progress in understanding the molecular events underlying human renal diseases, but there has been recent clarification by a consensus conference [2]. This review will be restricted to DNA and mRNA detection in renal tissue. We will not consider genetic mutations, such as those present in Alport's disease, since the gene defect is present in all somatic cells and analysis can be performed with circulating cells

Combined AGE inhibition and ACEi decreases the progression of established diabetic nephropathy in B6 db/db mice

The accumulation of advanced glycation end products (AGE) is a key factor in diabetic nephropathy (DN). Pyridoxamine inhibits AGE formation and protects against type I DN. Herein we tested: (1) whether C57BL6 db/db mice as a model of established type II DN resembled patients treated with drugs which inhibit angiotensin II action; (2) whether pyridoxamine was effective as a single therapy; and (3) whether pyridoxamine would add to the benefit of angiotensin-converting enzyme inhibition (ACEi) by enalapril. In first set of experiments mice were treated with ACEi (benazepril) and an angiotensin II receptor blocker (valsartan) combination for 16 weeks after the onset of diabetes. In second group, mice with established DN were treated with pyridoxamine for 8 weeks. In a third set, mice with established DN were treated with pyridoxamine and enalapril combination for 16 weeks. Benazepril and valsartan combination partially prevented the development and progression of DN. Pyridoxamine treatment, as single therapy, decreased the progression of albuminuria and glomerular lesions. The combination of pyridoxamine with enalapril reduced both mortality and the progression of DN. In conclusion, (1) C57 BL6 db/db mice are a model of progressive type II DN; (2) The combination of pyridoxamine with enalapril decreased progression of type 2 DN and overall mortality. Thus, pyridoxamine could be a valuable adjunct to the current treatment of established type II DN

Gender-specific effects of endogenous testosterone: Female α-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis

Young female mice on a C57Bl/6J (B6) background are considered glomerulosclerosis (GS)-resistant but aging B6 mice develop mild GS. Estrogen deficiency accelerates while estrogen replacement retards GS in young sclerosis-prone oligosyndactyly mutant mice on an ROP background. To explore the effects of sex hormones on glomerular structure and function in the context of gender and genetic background, we studied mice in which the estrogen-receptor (ER) genes α- or -β were deleted (α- or βER knockout (KO) and crossed into the B6 background. We also studied ovariectomized (Ovx) B6 mice given testosterone. Male and female βERKO and male αERKO mice had no glomerular dysfunction at 9 months of age; however, αERKO female mice displayed albuminuria and GS. Ovx prevented glomerular dysfunction in αERKO female mice by eliminating endogenous testosterone production while exogenous testosterone induced GS in Ovx B6 mice. Androgen receptor (AR) expression and function was found in microdissected glomeruli and cultured mesangial cells. Testosterone compared to placebo increased both AR expression and TGF-β1 mRNA levels in glomeruli isolated from female B6 mice. Estrogen deficiency had no deleterious effects on the glomeruli in B6 mice. Our study shows that genetic traits strongly influence the GS-promoting effects of estrogen deficiency while testosterone induces GS in a gender-specific manner