Clinical Science (2008) 114, 109–118 - D.Z. Levine - Rodent models of diabetic kidney disease and early hyperfiltration

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Clinical Science (2008) 114, (109–118) (Printed in Great Britain)

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Review article

Can rodent models of diabetic kidney disease clarify the significance of early hyperfiltration?: recognizing clinical and experimental uncertainties

David Z. LEVINE

Division of Nephrology, Kidney Research Centre, Ottawa Hospital and University of Ottawa, Toronto, ON, Canada M4Y 1R8

Key words: diabetes mellitus, diabetic nephropathy, glomerular filtration rate, hyperfiltration, nitric oxide, rodent model.

Abbreviations: AA, afferent arteriole; AMDCC, Animal Models of Diabetic Complications Consortium; DM, diabetes mellitus; DN, diabetic nephropathy; GFR, glomerular filtration rate; KO, knockout; L-NMMA, N^G-monomethyl-L-arginine; NOx, nitrate/nitrite; NOS, NO synthase; eNOS, endothelial NOS; nNOS, neuronal NOS; Nx, nephrectomy; ODC, ornithine decarboxylase; P_GC, glomerular capillary pressure; SMTC, S-methyl-L-thiocitrulline; SNGFR, single-nephron GFR; STZ, streptozotocin; T1DM, Type 1 DM; T2DM, Type 2 DM; TF, tubular fluid; TGF, tubuloglomerular feedback.

In the past, hyperfiltration and increased glomerular capillary pressure have been identified as important determinants of the development of DN (diabetic nephropathy). Recently, some basic research and clinical reviews on DN have omitted identifying hyperfiltration as an important risk factor. At the same time, different rodent models of DN have been described without and with documented hyperfiltration. In the present review, the importance of hyperfiltration is reassessed, reviewing key clinical and research studies, including the first single nephron studies in a mouse model of DN. From clinical studies of Type 1 and Type 2 diabetes mellitus, it is clear that many patients do not have early hyperfiltration and, even when present, its contribution to subsequent DN remains uncertain. Key mechanisms underlying hyperfiltration in rodent models are reviewed. Findings on intrarenal NO metabolism and the control of single-nephron GFR (glomerular filtration rate) in rodent models of DN are also presented. Characterization of valid experimental models of DN should include a careful delineation of the absence or presence of early hyperfiltration, with special efforts made to establish the specific role hyperfiltration may play in the emergence of DN.